CDKL5 ALL IN(VOLVED) 2025

1. Intro: Back in Rome

The first CDKL5 conference that I attended happened to be the patient meeting in Rome in 2017, where the CDKL5 Alliance was started. I am a neuroscientist and I was already working with patient foundations for related disorders, so I wanted to learn about CDD. I remember meeting some Spanish families (my country) who quickly explained me the disease. Also seeing Marinus on stage talking about a very small trial that they were running in CDD with their experimental drug ganaxolone. And I remember Antonino Caridi, a CDD grandpa, who took the initial leadership of the patient Alliance and welcomed us from stage.

 I ended up joining the Loulou Foundation in 2018, so having the CDKL5 Alliance meeting return to Rome in 2025 felt very special. We were back in the same place, but everything about CDD is now immensely larger: the size of the community, the treatment pipeline, and the number of people working on it.  And Antonino still looks the same.

The ALL IN(VOLVED) conference started Friday June 27th, with families catching up with each other, and meetings of the national patient group leaders and also with the pharma representatives. To give you some numbers, we had over 300 participants, with 41 people with CDD and many siblings who made the conference very enjoyable. In total we had participants from 24 countries or territories! in alphabetic order: Albania, Australia, Austria, Belgium, Brazil, Bulgaria, France, Germany, India, Ireland, Italy, Japan, MENA, Netherlands, Philippines, Poland, Romania, Slovakia, Spain, Sweden, Switzerland, the UK, Ukraine and the USA. That’s why we call it the Global Alliance. And we had 9 pharmaceutical and biotech companies supporting the meeting. Just hearing these numbers would have blown the minds of the 2017 participants.

Then on Saturday 28th we started with a series of science talks for all attendees, where we reviewed the disease, the natural history studies, the pipeline, and learnt about different therapeutic modalities and where they are. We called these the ALL IN(FORMED) sessions.

We also had a presentation from the team at the Pediatric Therapy Center High Hopes, in Dubai, because the non-pharmacological therapies are so far the best therapies that we have for kids and adults with CDD. They showed us best practices to improve strength and mobility and promote neuroplasticity in these kids, and talked about a “multidisciplinary team with a family-centric approach” with parents as co-therapists. 

For the afternoon we split into two tracks. I stayed with the scientists and the pharma companies in a partnering session where we learnt about specific programs on new therapies and model systems for the disease. I will mention these in my summaries below but without much detail, given that this track was designed to be only for scientists and not open to families. The parallel track for families included biomarker sampling and pet therapy with a dozen of beautiful dogs, which made us, scientists, very jealous. 

And we closed the conference on Sunday June 29th with the ALL IN 1 COMMUNITY session where the families took the stage and we all listened.

I will summarize below the main news from the scientific sessions, and some of the main messages from the families that I found particularly impactful. Please keep in mind that I am looking at the therapeutic progress as a scientist, not as a parent. And this is not the entire summary of the ALL IN(VOLVED) CDKL5 Alliance conference, so apologies in advance for the parts that I might be missing.  

2. Science: small molecule drugs

The first generation of treatments developed for CDD are anti-seizure drugs. That’s because CDD is one of the genetic syndromes that comes with the highest seizure frequency, and there is no good drug to control those seizures, so we really need something better.

 In 2017 in Rome, Marinus presented data on 4 patients with CDD taking ganaxolone, FOUR. Three out of four had improved, the fourth one didn’t, but it looked promising. Their plan was to recruit more patients.

By the time we met back in Rome for the ALL IN(VOLVED) 2025 conference, we know that the Phase 2 trial included 7 patients and was successful, that it would be followed by a global Phase 3 trial with more than 100 patients also successful, that then Marinus succeeded at getting ganaxolone approved for treating seizures in CDD in the US and Europe, and that Marinus was later acquired by a larger company called Immedica Pharma who was now with us in Rome at the conference. Change and progress can seem slow looking forward, but quite fast when you look backwards.

Carol-Anne Partridge is a CDD mum (and leader of the UK patient group) and she presented a study designed to convey better to governments and payers the severity of CDD. This is very important because ganaxolone is the first drug approved for CDD, so when authorities evaluate their reimbursement decision on ganaxolone they are learning about the drug AND the disease at the same time. And because of this learning curve, ganaxolone is still only commercially available in the US. The study surveyed 132 families, and showed that 96.7% of patients are taking anti-seizure drugs, and that if you measure the health-related quality of life of the CDD patients as reported by their parents from 0 (a state comparable to being dead) to 1 (representing full health), the average is 0.18. The survey used the methodology that payers want to see, and was designed to “speak” to them. I think the message is loud and clear about the need for new medications.

The biggest news of this conference came from our second Phase 3 trial in CDD: UCB Pharma issued a press released the first day of the conference announcing that the Phase 3 trial with fenfluramine for treating seizures in CDD was successful, both in efficacy and safety, and that they will be moving forward to request an approval for CDD now (fenfluramine is already approved for two other syndromes). If everything goes well, this will become the second drug approved for CDD. And thank you UCB for the perfect timing with the announcement, we all got to celebrate together.

And what comes after two global Phase 3 trials? another global Phase 3 trial. The company Longboard (part of Lundbeck after an acquisition) is developing a second-generation fenfluramine, called bexicaserin, that is already in Phase 3 trials in the US and is adding many more countries world-wide progressively this year. Interestingly this drug is bringing together into the same trial all of the rare epilepsy syndromes, that are often called “DEEs”, and because people with CDD often have many seizures it means that many will qualify for this trial. It asks for a minimum of 4 countable seizures a month, and ages 2 to 65. In Rome, we had Dr Marina Trivisano present an update on this program and show us the map with all the countries in the trial. You can see more information online if you look for the “DEEp OCEAN” trial, and I encourage you to ask your neurologist about it if you are interested.

These first three large trials were for seizure medications, but I also explained in my presentation about the CDD pipeline that after these trials we are moving into therapies that treat the disease, not the symptom.  And this includes not only the gene therapies (more about this in a minute) but also small molecule drugs that act on the most important targets of CDKL5. What we call “small molecule drugs” are the regular medicines that are taken orally like a pill or a syrup and that are made of a chemical compound – not something big like a virus or a protein. And because the work of the CDKL5 protein in the cell is to turn on or off other proteins, acting like a switch (that’s what kinases do), it is possible for scientists to design small molecule drugs that can bind to those proteins now, and turn them on or off as they needed.

In the morning session I introduced that concept, and I called it precision medicine because those drugs are designed to correct some of the key targets of CDKL5. And later in the afternoon during the partnering session we had a presentation from Prof. Massimiliano Bianchi who is developing one of those precision medicine approaches, with drugs that target the cytoskeleton (more of why that’s important for CDKL5 HERE in section 1).

3. Science: gene therapies

 There are several gene therapies in development to treat CDD, and we hope that they will get to clinical trials in the near future. A gene therapy uses a virus to deliver a copy of the CDKL5 gene to the brain, so it is made of the outside of a virus (to help it get into brain cells) but inside it doesn’t have virus DNA, it has the CDKL5 gene.

Dr. Stuart Cobb is one of the inventors of a gene therapy for Rett syndrome (with the gene MECP2) and gave us a beautiful lecture on how gene therapies work. In his words: “it is an easy concept, but with complicated execution”. It essentially follows four steps: make the virus, cure a mouse, check for toxicity in monkeys, and then go to clinical trials. He explained how in Rett syndrome they are already in clinical trials, and they are seeing clinical improvements. And two days after his talk, the company developing his gene therapy announced that they are progressing to Phase 3 trials with their gene therapy in Rett syndrome.

Some years ago ,we thought that gene therapies for CDD would be in clinical trials by now. Ultragenyx had said at the 2022 CDKL5 Forum that they hoped to be in trials in the following year. But that hasn’t happened yet, two and a half years later, so I know that has disappointed many families who have been counting how old their kids will be by the time the gene therapies arrive to trials.  And that premature announcement has probably also made the other gene therapy developers refrain from speaking too soon about their timelines, to not risk disappointing the community once again. As a result, we are still a bit in the dark about how many gene therapies are being developed for CDD and how far along they are.

Majid Jafar and I (both from the Loulou Foundation) mentioned in our presentations that there are multiple gene therapies in development for CDD, but it would have been much better to get some of the companies present an update. Even without stating timelines, seeing the progress that they are making would have been and influx of air for the 300+ family members in the room.  

We did have two presentations dedicated to a special type of gene therapy for CDD: a gene therapy designed to open up the second CDKL5 gene copy. For background: because males only have one X chromosome, female cells only use one of our X chromosomes and turn the second one into a tiny little ball that is not read. That way, both males and females have one functional X chromosome.  Which X chromosome gets inactivated is totally random and is different for each cell. What this gene therapy does is to carry inside of a virus the instructions to read the second copy of CDKL5, the one in the inactive X chromosome. And because girls with CDD have always one good CDKL5 gene copy (the other one is mutated) this gene therapy can help each of their cells read the two copies, one of which is good, and that’s all we always needed! Dr. Kyle Fink is leading this program and told us that they are now making “clinical grade gene therapy” to start the safety experiments in monkeys that come prior to trials.

4. Science: Enzyme Replacement Therapies

 We also had a lecture on how enzyme replacement therapies work. Prof. Elisabetta Ciani explained very nicely how an enzyme replacement therapy consists of making “lab-made CDKL5 protein” to then give it to neurons. This is a good idea because CDKL5 is an enzyme, and other brain enzymes have been successfully adapted to enzyme replacement therapies. But as Stuart had said earlier that morning, this is also “an easy concept, but with complicated execution”. Elisabetta had succeeded at making a modified CDKL5 (so that it enters cells) in her lab and using it to treat CDD mice, but the same methods that worked for mice don’t work as a medicine for people, and here is where the challenge has been.

Prof Maria Luisa Tutino, who is both a CDD mum and a protein scientist, has been trying to make as many changes as needed to the CDKL5 protein to make it suitable as a lab-made protein therapy. The first-generation lab-made CDKL5 only goes to the “stomach” of neurons, so they eat it instead of using it, and she is currently working on a second-generation approach for which she has received a 1 million Euro grant. This one is clearly a very complicated therapeutic approach, but one worth fighting for.

5. Making it easier to develop treatments and to run trials

Before getting to trials, we need to believe that the treatment is going to work. How do we check that it could work? by testing it first in animals with the disease. And once we get to trials, we need to confirm that the treatment works, this time in patients. And how do we see if it worked in patients? by measuring clinical changes.

At the 2025 patient conference we got updates on animal models and on clinical change measures.

We reviewed the animal models in the partnering session, with Prof. Leonor Cancela showing us the zebrafish model of CDD (and small molecule screenings that she is running), María del Carmen Martín showing us the drosophila model of CDD (which has lots of seizures) and the Ulysses Neuroscience team showing us their CDD mouse model testing service. That means we have the entire toolbox to run preclinical trials in CDD animals.

And we got updates on the studies to measure clinical changes during the big morning session with all families in the audience, because all CDD families are critical players in these clinical programs.

Prof. Tim Benke gave us an update about the disease, and also updated us about the ICCRN natural history study in the US where they are developing a single scale to measure the global severity of CDD for each patient. And Dr. Xavier Liogier told us about the international CANDID study that is managed by the Loulou Foundation, where we have been able to see that there are many seizures at all ages, that most of the developmental improvements are seen in children under the age of 6, and that there are several scales to measure different disease domains (like cognition, communication, behavior or motor skills) that could be already used in trials. These two studies have enrolled more than 200 patients together, and participating in these studies means several hospitals visits over several years, so it is a big effort by the patients and their families and it would be impossible to design complex clinical trials (like for gene therapies) without all of you.  

While the natural history studies help us know how to measure EXTERNALLY how a medicine might be helping, we use biomarkers to measure the INTERNAL changes. At the Rome conference we saw an update on the ELPIS global biomarker study by Prof. Massimiliano Bianchi, where they track changes in proteins in blood that tell us what is happening in the brain. And we also had a presentation by Vita Cardinale, who won the conference poster competition and was invited to give a talk on her project where they look at biomarkers in saliva from patients. These biomarker studies are made possible by more than 100 volunteer patients and their families who are helping these scientists identify the internal measures of change. 

By the way you might wonder how blood or saliva can tell us what is happening in the brain.  The answer is that neurons talk to each other by sending out little bits of neuron that contain proteins and RNAs almost like sending a letter by post to each other. The inside of those little bits tells the recipient how that original neuron was feeling. Sometimes the recipient is a neighbor neuron, but sometimes those letters travel so far that the recipient is a scientist that can pick it up in liquids like blood or saliva and read that letter.  Science can be very cool.

6. Voice of the community

Patient conferences can be very emotional, with many highs and lows. In Rome we shared three days with families in very different situations, from those who had their little kids with CDD taking their first steps, to parents who have lost their children. So it was only fair that after the main conference day families took the stage.

During this final session we listed to #1minuteofhope videos where parents from all over the world told us what hope meant for them, and asked the audience “what does hope mean for you?”. We had videos from Italy, Peru, USA, Canada, Japan, Ukraine, MENA, and France.

Mais Kanan from CDKL5 MENA started the day, and Majid Jafar from the Loulou Foundation gave us a recap for how much progress has happened since his first daughter Alia got diagnosed with CDD in 2014. His was a message of hope, hard collective work that got us to where we are, and perseverance to get where we need to be.

We then got to hear from two siblings, starting with Iman Jafar who told us about how much she loves having Alia as her older sister, and how the first word that she ever spoke was “up” after hearing so often everyone tell “up!” to Alia to help her with her motor skills. And later we heard from Alessandro Caridi, who had a harder story as a sibling to a sister with CDD, but who also reminds us that the experience of every family and every person is unique, and to not underestimate the impact of this severe disorder on everyone around.

 Dr Michela Fagiolini spoke about the possible future and dreams, from her experience working as a scientist in CDD and related diseases. She had some really good messages for families, like “drugs tailored for CDD and gene therapy are coming. These are not just abstract hopes, they are real and moving forward”. And how “it cannot be one person or one lab or one family, everyone is needed, and you are not alone”.

 Then CDKL5 Spain shared two voices, one from a founder parent, and one from a more recently diagnosed family. Sandra Pérez spoke about being one of the “5 families and 5 stories” who created the Spanish association in 2014, and how one of the main missions of the group is and was to welcome new families, because they know how it feels to receive a diagnosis that changes everything, and how important to know that you are not alone. Then Manuel Vigara spoke about how thankful he was to those first 5 families who were “a light in the middle of dark, and whose steps opened our path”. He explained that the word “rare” often means no resources and no answers, and asked for the science community to keep dreaming and progressing, because “each hour in the lab is a thread of hope for millions of families” and “each small progress is a miracle in the making”.

 We heard from the Fondazione Telethon in Italy about their support to rare genetic patient groups, and how “tenacity” is the identity of the Italian association and host of this meeting, CDKL5 Insieme Verso la Cura.

 Last Barbara Verdirame, president of CDKL5 Insieme Verso la Cura, took the stage to thank everybody, from the families to the volunteers to the scientists and the doctors and the industry representatives in the room and everyone who supported the conference. Because in the end it is only through that massive collaborative effort that we get to advance medicine.

 And I want to close this summary by capturing some words from Antonino Caridi, who opened the conference by reminding us of how far the International CDKL5 Alliance has come since it was founded in Rome in 2017, how “hope” is not a passive word, but one that gives us the courage to transform the injustice of CDD, and that “the best is yet to come”.

Ciao a tutti!

Ana Mingorance, PhD

Disclaimer: I write these texts with the parents of people with rare epilepsy syndromes in mind, so excuse also my lack of technical accuracy in parts. And credit for the beautiful pictures goes to Massimiliano Marcoccia and the great team from CDHL5 Insieme verso la cura.

AES 2024: THE FUTURE IS NOW

I often write a summary of the main lessons from the American Epilepsy Society meeting, but this year there was so much about epilepsy syndromes (which you also see referred to as Developmental and Epileptic Encephalopathies, or DEEs) that I didn’t have a chance to see many of the more general epilepsy presentations at AES, or even everything about DEEs!

Therefore this summary is not intended to be a summary of what was presented at AES, but simply the highlights of what caught my eye at the conference and where I see the field going.  

You can see my summaries from previous years at AES here: 2017, 2018, 2019, 2020, 2021, 2022, and 2023.

1 - THE FUTURE IS NOW: TANGIBLE PROGRESS IN DISEASE-MODIFICATION

In 2022 I talked about crossing the line from developing treatments for symptoms, to developing treatments for the cause of the disease. And the line from focusing on a few syndromes only (those with the most patients), to seeing treatments in development for many more. I called that escape velocity.  

At that time in 2022, that progress was illustrated by ongoing trials for Dravet syndrome (SCN1A haploinsufficiency) and preclinical progress in other DEEs. We were not there yet, we were just taking off. 

After a slower 2023, 2024 caught up with the speed and delivered us a fantastic year for DEEs, and in particular for Dravet syndrome. This was the first classic DEE (if we don’t count other neurodevelopmental disorders like Angelman syndrome and Rett syndrome, more on this below) to cross the line between having promising treatments for the cause of the disease in development, to having clinical proof of disease-modification.

For Dravet syndrome, 2024 has marked a before-and-after in therapy development, and two news at AES made all this difference.

First Encoded Therapeutics presented during the Dravet Syndrome Foundation Roundtable the evening before AES and announced that they have already dosed 5 patients with their gene therapy ETX101 using a virus to deliver a transcriptional activator for SCN1A. They expect to be able to share some safety and efficacy data in the second half of next year. Encoded is only recruiting very young children for their POLARIS Phase 1/2 program in Australia, the US and the UK, as young as 6 months of age. This means that if this gene therapy is successful, these might be the first few kids with Dravet syndrome that will be spared from developing the disorder, or that will only develop a milder form of it. And as a reminder, Dravet syndrome like all other DEEs comes with neurocognitive delay, behavioral problems, motor problems, drug-refractory epilepsy and (in this case) a high rate of seizure-related mortality. Because it can often be diagnosed during the first year of life, a gene therapy like this one could be used in the future soon after diagnosis and PREVENT the development of Dravet syndrome. At least that would be the ultimate success scenario.

But what if you already developed Dravet syndrome? That was the second big news at the conference, and for me the highlight of the entire meeting and of my 13 years working in this disease. A few days after the announcement from Encoded, Stoke Therapeutics showed the complete results from their Phase 2 in children and teenagers ages 2 to 18 with zorevunersen (STK-001), an ASO designed to increase the levels of productive SCN1A mRNA, including 24 months follow up of these patients, and we learnt that:

• Stoke already identified the right dosing for the Phase 3 trials: 2 or 3 loading doses of 70mg followed by 45mg maintenance doses every 4 months.

• They see sustained seizure reduction of over 80% at that optimal dose (this is more than fenfluramine, and with half of the patients already on fenfluramine!)

• They documented growing improvements after 12 months and 24 months in …wait for it: receptive communication, expressive communication, personal skills, interpersonal relationships, play and leisure, coping skills, gross motor and fine motor skills. That’s it, the entire Vineland-3 scale improved in all domains, getting even better into the second year of treatment, while we know from the natural history studies that these patients don’t make improvements in any of these skills within a year.

To better understand the transformational improvement that these numbers meant, one of the principal investigators from the Phase 2 trial showed some videos of the before and after of a 12-year-old treated with zorevunersen. In my experience, what I saw is what many Dravet syndrome families have described over the years as “the cure”, and what we can medically call a truly life-transforming improvement across all the disease domains. Here is some description for what we saw in the video:

• Before treatment the teenage girl had problems with motor coordination and balance, hesitation in movements when trying to kick a soccer ball and ataxia. She looked like many people with Dravet syndrome at her age. Yet the video of her playing soccer 8 months after treatment with zorevunersen showed a completely different posture, much more fluid, with balance, even able to control the ball with her foot to center it before kicking. This level of improvement in this short amount of time was not something I thought would be possible, and that’s the power of seeing videos. And then again, remember that patients on zorevunersen keep getting better over time and this improvement was already within the first year.

• We also saw videos of her buttoning her shirt with much improved fine motor skills, and then some videos of her talking to her doctor and following some basic directions that showed a dramatic difference between a shy distracted kid who could not keep much eye contact or follow basic instructions as in “touch my finger and then touch your nose” to a completely transformed teenager within a year, who would sit up and cheerfully follow the instructions and chat with her doctor about her school and favorite subject. And she went from 5 seizures a month to 1 or 2 seizures a month so this improvement is clearly related to the genetic upregulation and not to any dramatic effect secondary to seizure reduction. The transformation is hard to explain with words so I hope you can see the video in Stoke’s website (during this first month you can see it here) and how she does not look like the same kid after 8-12 months of treatment.  

• Stoke said that the improvements that we saw in this girl map into the Vineland as an average patient after treatment with zorevunersen. So this was not a super-responder case, this was a representative patient.

This clinical trial with zorevunersen in Dravet syndrome is the first proof of disease-modification in a DEE. The first successful transition from seizure management to SYNDROME management, by targeting the root cause of the disorder. Any improvements in cognition or behavior (mainly focus) that we have seen over the years with seizure drugs like fenfluramine dwarf in comparison to the magnitude and sustained progress that we are now seeing with zorevunersen. Finally the future is now.

The results with zorevunersen in Dravet syndrome are so strong that I worry about the possibility of unblinding during the Phase 3, because presumably (the design has not yet been announced) the Phase 3 will be about one year long yet clinicians from the Phase 2 report clear improvements as soon as 6 weeks into the trial. Unblinding due to efficacy already happened in the spinraza trials in SMA, and indeed zorevunersen is looking like a spinraza in the making.

And now that we know what the human brain can do, and how much plasticity is still in it if only we can come with the right genetically-targeted treatment, we look at the other DEEs and ask when will they get their Stoke moment.

For SCN2A developmental and epileptic encephalopathy, Praxis is developing an ASO to downregulate the ion channel expression in cases of gain-of-function mutations (elsunersen), but it is so far only used in a few cases under emergency use. My eyes are on the gene therapy from Capsida for STXBP1-related disorders, which is on track to get an IND in the first half of 2025 and it will be an intravenous-administered gene therapy to restore STXBP1 levels, so it is a first-of-a-kind for the DEE world and even for the entire neurology field. SYNGAP1 held a scientific conference the day before AES and they also seem to be next in line for disease-modifying trials, with the ASOs including the one from CAMP4 Therapeutics in toxicology evaluation which is the last step before filing for an IND and several other programs in development. CDKL5 deficiency disorder is also preparing for next-generation gene therapies, and we saw a presentation from UCDavis with a viral-delivered epigenetic gene therapy that can open up the inactive X chromosome to specifically drive expression of the CDKL5 gene copy and that is also in late preclinical stage.

So the future is now for Dravet syndrome, and around the corner for several other DEEs. Based on the speed of progress in Dravet syndrome, I estimate that the AES conference in about three years will probably be the one with clinical results for disease-modifying therapies in multiple DEEs since we are on track for multiple trials to start in 2025 and 2026. But hey, maybe things go even faster now that we know (and investors know) that cures, or life-transforming improvement across all disease domains, are a real possibility.

2 - BEYOND SEIZURES IN DEEs

I mentioned before that Dravet syndrome is not alone, and that if we broaden our focus to include other neurodevelopmental disorders that are often less featured at AES (despite also having epilepsy) we see that 2024 has been an unprecedented year when it comes to showing neurodevelopmental improvements in monogenetic disorders with ASOs and gene therapies:

• In Angelam syndrome, Ultragenyx and Ionis have announced that they are progressing to Phase 3 trials with their ASOs that increase UBE3A expression. Ionis showed data from their Phase 1/2 HALOS showing improvements in communication, cognition and motor function in Angelman patients ages 2-50. Ultragenyx also released data this year from their Phase 1/2 trial in Angelman patients ages 4-17, also showed rapid improvement across many disease domains.

• Some diseases are not obvious targets for ASO treatments, and in Rett syndrome we have one of the first neurodevelopmental disorders to get clinical data from gene replacement gene therapies. Neurogene recently shared data from the first Rett syndrome patients (ages 4-7) treated with their viral gene therapy, also showing improvements in fine and gross motor skills, communication and cognition, while girls with Rett syndrome don’t re-gain skills after their early regression. Neurogene run into safety problems at a higher dose of the gene therapy, but the lower dose had substantial efficacy and should be a viable dose moving forward.

This brings us to 3 neurodevelopmental disorders that this year reached proof of disease-modification with genetically-targeted treatments, and their value goes beyond Angelman, Rett and Dravet syndrome because what they tell us is that the brain keeps much plasticity that is ready to go as soon as we get the right therapies.

To be able to document these improvements, companies had to move beyond seizure counting and figure out which scales could be used for Phase 3 trials in these disorders to document non-seizure improvements. It seems from Dravet syndrome that the non-seizure scale for the Phase 3 will be the Vineland-3 scale, while in Angelman both Ultragenyx and Ionis are choosing the Bayley scale for their Phase 3 trials. In fact all these companies were able to interpret their open-label Phase 1/2 trials because there had been previous efforts to document the performance of this type of scale in a particular type of Natural History Studies called endpoint-enabling studies, showing minimal or no skill development beyond certain age for these disorders. None of these findings would have been possible without those natural history studies.

In Dravet syndrome, the endpoint-enabling studies were run by Stoke and Encoded specifically targeted to the ages of their interventions. Encoded deep-phenotyped Dravet patients under 5 in their ENVISION study, and was able to show an inflection point around 2 to 2.5 years of age when patients slow down in their neurodevelopment despite the best standard of care. Stoke further extended this age range in their Butterfly endpoint-enabling study to show lack of changes in seizure frequency and skills over 12 months in this population, which leads to a growing neurodevelopmental gap when compared to the neurotypical population. These results were presented at AES as the reference to interpret the progresses that we are now seeing with the disease-modifying therapies and also to justify trial design.

While in Dravet syndrome those studies were initiated and run separately by two biotech companies, in CDKL5 deficiency disorder the Loulou Foundation was able to convene several companies in their space to participate jointly in a single endpoint-enabling study called the CANDID study by creating a pre-competitive consortium. This year the CANDID consortium presented the baseline results from this study at AES, which includes scales like the Vineland-3 and the Bayley that seem to be becoming the frontrunners for Phase 3 trials in this space, and the study is now collecting longitudinal data for all these scales.

And other communities chose to run before the companies in their space were ready, and to launch endpoint-enabling studies to start documenting the suitability of those preferred-scales for their particular disorder and their progress over time. This is the case of the STARR study for STXBP1-related disorders and the ProMMiS study for SYNGAP1 which were also presented at AES.

These studies are key for a disease to be “trial ready” for beyond-seizure trials, and key for the transition from treating only seizures to treating the syndrome.

3 - BEYOND THE LARGEST DEEs

At this point you are probably tired of hearing me mention the same group of DEEs over and over. That is because they have the most patients and the most advanced pipelines, but 2024 has been, again, a very different year when it comes to going beyond the top DEEs.

It started with Longboard pharmaceuticals announcing last summer that they have agreed with FDA to run a Phase 3 trial for bexicaserin (a second-generation fenfluramine) in “all DEEs” as opposed to cherry picking two or three of the largest syndromes. Longboard, recently acquired by Lundbeck, was one of the stars at AES and I have to praise them for making the time to meet with as many of the rare disease advocacy groups as they could during the conference, which is NOT an easy task when you have expanded your scope to include literally all DEEs!

The first-ever Phase 3 trial for “all DEEs”, called DEEp OCEAN (with bexicaserin), has already started in the US and will open up sites in Europe and beyond in this coming 2025. And at least one other company has already announced that they will be following on these steps: Praxis expects to being enrollment into the EMERALD trial with relutrigine (a next-generation sodium channel blocker) in the first half of 2025.  

This means that for so many other DEEs, include very rare ones, the future of being chosen for clinical trials is also now, and arrived in 2024. What a year.

These combined “all DEE” trials are possible because they are counting seizures, and their approval will be for the treatment of seizures in DEEs. But we were just talking about how DEEs are “neurodevelopmental disorders with seizures” and we really need treatments that address the neurodevelopmental part.

I expect the next few years to get us closer to clinical trials across DEEs with treatments that can target some of the core biology of the diseases and that will need to show improvement in non-seizure outcomes. One example are genetic approaches like the one from Tevard Bio, that rescues non-sense (premature stop) mutations regardless of the gene that has them. Tevard was present at AES including at the SYNGAP1 conference. Another example are small-molecule drugs that might improve seizures and non-seizure outcomes like the KCC2 activators (some were presented at AES, other companies were in attendance but not presenting). For all those, we will need to identity clinical scales that work across different DEEs and to come up with a “core outcome set” for the non-seizure aspects of DEEs which might be a combination of some elements of the Vineland-3 and the Bayley, and perhaps other scales. Here again, we rely on those endpoint-enabling studies that the different communities are running to help us unlock the next-generation treatments for DEEs that can work across disorders and not only on their seizures.

But that is the future for the next few years. Today we celebrate a 2024 that was unprecedented in terms of tangible progress and change, with Stoke’s data adding to the news on Angelman and Rett syndrome that makes us believe in disease-modifying treatments, and with Longboard opening the door for innovation to reach everyone. What a year.

Ana Mingorance, PhD

Disclaimer: I write these texts with the parents of people with rare epilepsy syndromes in mind, so excuse also my lack of technical accuracy in parts.

MAIN LESSONS FROM THE 2024 CDKL5 FORUM

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For the past ten years, the Loulou Foundation has hosted an annual meeting, the CDKL5 Forum, where scientists and drug developers working on CDKL5 Deficiency Disorder (CDD), together with representatives from patient organizations, meet to discuss the latest developments in the field and to advance towards treatments and cures. You can find summaries from some of the last meetings here: 2018, 2019, 2020, 2021, 2022 and 2023.

The 2024 CDKL5 Forum edition took place October 28-29 in Boston, and will stay in Boston next year for the 2025 edition. This was the largest Forum to-date, with over 200 participants including representatives from 33 companies and 18 national patient groups. This was also a special edition, as this was the 10th CDKL5 Forum (with the first one taking place 9 years ago). I will try to summarize the main take-home messages from this year’s Forum. This won’t cover all the presentations, but rather focus on the main themes that we saw and the main progresses – which are always many.  

1. New interesting learnings about CDKL5 biology and CDD

Image: Researcher Maria del Carmen Martin Carrascosa (CIPF), Forum Director Dan Lavery (from Loulou Foundation), and research doctor Josephine Thinwa (UTSouthwestern).

Sila Ultanir introduced a session on the biology of CDKL5 saying that a few years ago we only knew that CDKL5 was missing, so we could only think of putting back CDKL5 as a way to cure the disease. But today we know much more about what it does in cells, so this opens up different entry points to try to correct some aspects of the disease without needing to put back CDKL5 yet.

We learnt from Oguz Kanca from Baylor that there are patients with gain of function mutations in CDKL1 and CDKL2 that have neurodevelopmental syndromes so CDKL5 is not the only important gene in this family. And we learnt from Maria del Carmen Martin Carrascosa that fruit flies without CDKL5 have spontaneous epilepsy and repeated stereotypies so they seem to capture better the lack of CDKL5 that mice do. However in any animal that came in evolution before jaws appeared (yes, jaws), CDKL5 is acting almost like a CDKL1-4 which don’t have the full scope of functions of our CDKL5.   

One of those potential redundant CDKL genes is CDKL2, so last year we considered if increasing CDKL2 could be a possible therapeutic approach when CDKL5 is missing. This year Kevin Dempster presented what happens if you get a mouse missing both CDKL5 and CDKL2… does it get even worse? The answer is yes but interestingly CDKL2 seems to only do SOME of the jobs that CDKL5 does in the cell, not all of them, notably not the job of changing activity of calcium channels and glutamate receptors. So in a way, increasing CDKL2 has the potential to rescue some of the consequences of missing CDKL5, but other consequences still need to be addressed separately, as is the case of still needing to inhibit Cav2.3 (more on this later).

On the biology side, we learnt from Josephine Thinwa that CDD patients might be more sensitive to viral infections, causing a larger inflammatory response, and from Lauren Orefice that lack of CDKL5 in different sensory neurons makes people with CDD more sensitive to textures, sensations (tactile sensitivity, like a tag in your clothes) and more prone to GI pain. All these seem to be sensory problems caused by CDKL5 lack in sensory neurons.

There were also different presentations during the Forum and pre-Forum meeting that point to the thalamus as an important brain part in CDD, as part of the thalamocortical connection. For example Rachel Oren presented that the cortical Visual Impartment is not in the eye (which is fine) or in the neurons that go from the eye to the thalamus, but somewhere later by the time the signal gets to the visual cortex. Another important brain component seems to be interneurons, shown by Tim Benke using a CDKL5 inhibitor in brain slices, which could help explain why some of the GABAergic drugs including ganaxolone are the best for CDD.

2. Beyond the research toolbox: the year of platforms

a. Cells and mice

One of the main goals of the Loulou Foundation early on was to make sure that any scientist anywhere in the world can work on CDD. This meant creating a collection of research tools like animal models and making them open-access. Can we see where CDKL5 is in this cell? Can we see if it is active? Can we see the consequences of missing CDD? And what does this mean about this organ physiology? we can’t answer this without cells and antibodies and mice.

This has led to a growing collection of animal models and cell models and antibodies which are available to the community. But this was perhaps the year of “platform as a service”, which is the next step once tools exist.

Image: slide from CDD mouse testing platform, slide from CDD iPSC-derived neuron platform, and researchers Liz Buttermore (BCH) and Jasmine Carter (Loulou Foundation) during the breakout session on iPS cells.

I want to highlight the iPSC-derived neurons from CDD patients which are running as a service at Boston Children’s Hospital Neuron Core led by Liz Buttermore, and the breakout session that Liz and Loulou Foundation’s Jasmine Carter led about the iPSC-derived models.

Liz walked us through all the crazy work that led to their very good in vitro epilepsy assay with patient-derived iPSC lines, and it was a great example of how hard is to standardize an assay of this type of have it be robust and reliable. Companies can now send their compounds to Boston to be run in this epilepsy-in-a-dish CDD model using microelectrode arrays.

We had a breakout session in the afternoon led by Liz and Jasmine to see how the academic and biotech community will want to work together in setting up these in vitro models. There were discussions about learning from each other successes and mistakes, and having a shared channel to ask questions since troubleshooting these models can get so tricky. The discussion was fantastic (and I’m sorry I missed the parallel breakout sessions).

Just like with cells, The Jackson Labs has set up a panel of mouse models of neurodevelopmental diseases that are now available for drug testing in a fee-per-service way. Rajat Puri presented data about their CDD mouse preclinical testing service, showing robust signal across mouse ages, mouse batches and even across lab researchers. Again, these standards are very tricky and it is powerful to have them available as a service as opposed to having to go through all the troubleshooting in each individual lab. The tests that I liked the most showed how bad CDD mice are at burying marbles and building nests, which are the mouse equivalent to activities of daily living for people.

And why are the services so important for companies working on treatments? Because having a mouse or a cell line available is like buying ingredients at the supermarket, we still need to cook them in the lab, but these in vitro patient models and complex behavioral mouse models are very elaborate and easy to get wrong, so having them running as a service is like offering restaurants where you can get the complex dish ready. It is much easier to go to a restaurant and order a paella than to spent two years learning how to cook a good one.

b. Patients

There is an observational clinical study in CDD designed to learn about clinical scales to measure symptoms other than seizures in trials, and to collect data that might serve as a control dataset for future clinical trials in CDD. It is called the CANDID study and I am very very proud of it, not only because I was part of the early team that saw the need for such study and got it started, but because it has evolved and it is now owned by the community. At the Forum, Xavier Liogier from the Loulou Foundation presented the results from the scales assessments in the CANDID study, which has more than 100 patients from the US, EU and MENA, and we learnt not only which scales could be used in a trial today for a gene therapy, but also the fact that 83% of patients would qualify for a trial if it asked for a minimum of 16 seizures per month. 83% IS A LOT! In other syndromes 25% or less of patients would have enough seizures for trials, and seizures are very likely to remain as the primary endpoint for trials, so in a way we have the perfect disease for clinical trials. This is important to know!

Image: Xavier Liogier (Loulou Foundation) presents an update on CANDID, and group discussion with doctors and patient representatives.

There was also a meeting for the CANDID study where Xavier and Maria Makarovskaya, the two professionals from the Loulou Foundation in charge of CANDID, asked clinicians in the study and representatives from the patient community about their experience in the study and their feedback. And this is where it became clear to me that CANDID was started by a small group of people, but it is now owned by a much much larger group, including the 112 patients that signed up and their parents, and all of the study investigators and their team of nurses and psychologists. This is huge, and a reason for many to be proud.    

There is also a large fluid biomarker effort that was discussed in one of the breakout sessions. A fluid biomarker is a way to measure something in blood or CSF or other body fluid that shows that a therapy is working. For example sugar levels in blood serves as a biomarker for diabetes, while cholesterol in blood serves as a biomarker for cardiovascular risk. Maurizio Giustetto from Italy is looking at saliva to measure little vesicles that neurons spit out to talk to each other and that could potentially be picked in saliva (crazy!). And there is an international collaboration called ELPIS led by Massimiliano Bianchi that is collecting patient blood samples to check for potential biomarkers in plasma. They already found some potential plasma biomarkers, I wrote about that last year, and one year later the program is expanding to more countries and is considering a sample collection of blood and saliva from patients and siblings (as controls) during the Rome 2025 patient conference. Stay tuned for more information about that.

3. Therapies: the now, the near now and the blurry future

At the beginning of the therapies session, Omar Khwaja who is a doctor who has treated kids with neurodevelopmental disease and then became a drug developer, provided an overview of the CDD pipeline today.

We have ganaxolone approved in the US and Europe, and the CDD patients also use often Epidiolex off label, because it is approved for LGS and because there is good Phase 2 data for CDD. So we “almost” have two drugs approved. We then have clinical trials with fenfluramine (in Phase 3) and bexicaserin (about to start Phase 3 for DEEs including CDD). After that, there is a group of four “almost ready for trial” programs including three gene therapies.

In Omar words, we’ve come really far in these 9 years since the first Forum, with an entire landscape of programs in development including disease-modifying genetic therapies in late preclinical stage and multiple drugs in trials or approved. I invite you all to see the older summaries of the Forum to see this progress, including former trials that didn’t progress like ataluren (negative data in Phase 2) and soticlestat (positive data in Phase 2 but not chosen by the pharma for a Phase 3).

a. The now

Images: Sabine Bongardt from UCB Pharma, Randall Kaye from Longboard, and a slide from Elisa Borghi’s presentation on the pre-biotic and pro-biotic supplement trial.

UCB Pharma presented the progress with the fenfluramine Phase 3 trial in CDD, which is probably closing recruitment at the end of this year. They are particularly asking for children ages 1 to 2 to participate, with room for about 20 in the trial. This is very exceptional, because trials often only start at 2 years of age and in a disease like CDD that can start as early as in the first weeks of life, those two years can mean over one thousand seizures before the child could start taking fenfluramine (or any other drug with a minimum age of 2 years!). So if you know any family with a one year old with CDD and uncontrolled seizures please let them know about this trial (more info about locations in the trial website) so that this trial will complete recruitment at the end of the year.

And as one trial ends another one starts. Longboard Pharma is developing a drug called bexicaserin that is a second-generation fenfluramine, and it is starting a Phase 3 trial combining all epilepsy syndromes and in particular the large ones (including CDD) for patients ages 2-65 with at least 4 countable seizures a month. They are aiming for 80 trial hospitals, potentially over 100, and to start recruiting really soon. So check with your doctors if Longboard has reached out to them about this upcoming trial with bexicaserin called DEEp OCEAN.

By the way, Longboard has been quite popular recently because of choosing to combine all the epilepsy syndromes (all the DEEs) into a single trial and they even recently got bought by Lundbeck, the pharma company that makes clobazam. So there has been a lot of momentum around bexicasein. And Longboard received the 2024 CDKL5 Forum Company Making a Difference Award and CMO Randall Kaye talked about seeing an amber light as a sign to speed up, not to stop. Longboard is speeding up to treatments for all DEEs, even though the difficulty of the task ahead could have made others want to slow down (or turn away). For us in CDD, their Phase 3 means another chance to access a novel molecule in development before it gets approved.

And at the Forum we also had a very interesting presentation from Elisa Borghi about a clinical trial with a mix of pre-biotic and post-biotic supplements, so “food for your microbiome” and “products that good microbiome would release”. Their research was started by the Italian patient family group, and it is now in a Phase 2 trial with CDD patients to see how it might improve GI function and epilepsy, which seems to have a GI component. What I like of this program is that if the trial is positive, families can directly access the supplement and don’t need to wait for lengthy regulatory approval and price reimbursement negotiations as is the case for drugs. And there was another company in attendance although not presenting that is also targeting the microbiome, but using the good bacteria (so it is not a pre- or post-biotic but a biological treatment!). I hope that next year we also have them present and learn more about clinical interventions in this gut-brain area.

b. The near now

I don’t know if you have realized that we have now three gene therapies and one small molecule program all past clinical candidate nomination. “Clinical candidate” is how we call a drug or therapy that is already done with optimization and tweaking, and that scientists then transition to safety and toxicology testing in animals other than mice so prepare to file and IND (a permission to start trials).

Images top: Ultragenyx’s Emil Kakkis and slide from their gene therapy program. Slide from Lario Therapeutics.

Images bottom: UCDavis’ gene therapy slide and Kyle Fink. Slide from the Loulou Foundation and Penn gene therapy presentation.

One of these is the gene therapy for Ultragenyx, which CEO Emil Kakkis explains that already reaches enough number of neurons in pigs (and is safe) to look ready for trials, and in a few months they hope to make a decision about potential methods to improve the brain distribution of the virus prior to then progressing to an IND. He also showed us great results that Ultragenyx is having in other three neurological diseases like Angelman syndrome where Ultragenyx is progressing to a Phase 3, and left us with the hopeful learning that “the brain is more plastic and more capable than we think”.

A second program in this near now category is the gene therapy from the Loulou Foundation, funded via its subsidiary Elaaj and created by the Gene Therapy Program at UPenn under the direction of gene therapy super-expert Jim Wilson. Jim recently left Penn to start a company called Gemma Therapeutics so the presentation of this gene therapy was done by Janine Lamonica, the leading scientist for this program at Gemma. This gene therapy looks like a solid clinical candidate that is ready to take forward. Both the Ultragenyx and the Loulou Foundation gene therapies use a copy of human CDKL5 gene inside of an adeno-associated virus (AAV) and are administered via injection into the cisterna magna, the big pool of CSF that you can access at the nape, in between your neck and your skull (via ICM). So these gene therapies are fairly similar.

A third gene therapy that is now moving into toxicology is the X-reactivation CRISPR 2.0 approach from Kyle Fink at UCDavis that uses a modified CRISPR to find the second CDKL5 gene in cells, which is inactivated as part of the inactive X chromosome, and makes the cell read it. Instead of find-and-cut this is a find-and-activate type of CRISPR, and to get it to neurons the scientists are using two AAV virus, each carrying half of the CRISPR sequence (actually millions of virus of each, not only one of each, so that when they infect the same neuron they can make the find-and-activate type of CRISPR). Their mouse rescue data is beautiful and they are seeing success in adult female mice, again showing that it is probably never too late for CDD!

And the small molecule program that has already nominated a candidate (a final molecule) is the Cav2.3 inhibitor program from Lario Therapeutics. Two years ago we learnt that Cav2.3 is a channel that makes glutamate neurons fire and that is usually controlled by CDKL5 as a break, bringing down its activity. In the absence of CDKL5, Cav2.3 is too active and excitatory neurons go crazy, so we would need inhibitors. Last year we saw some early data with those inhibitors made by Lario, and this year they showed us a beautiful dose-response activity in glutamatergic neurons made from CDD patient cell lines, so the more drug the more correction of crazy excitation. This is a drug, not a gene therapy, which makes it very attractive to combine with other treatments.

c. The blurry future

Here is where we have all the other therapies including gene editing (the one that fixes your DNA sequence, by David Liu), or the gene therapy that fixes non-sense mutations (by Tevard), or the early-stage ASO approaches that are being attempted to rescue CDKL5 or increase CDKL2, and even the efforts to make CDKL5 protein in the lab to then give it to the brain (enzyme replacement therapy). There are also talks about changing the virus type to the ones that can be administered via blood injection and then cross to the brain, so that we don’t need to inject gene therapies directly into the brain. Many people are working hard in all those avenues, but we don’t know IF any of them will eventually get to trials or WHEN they might get to trials. So what we know is that today, the best gene therapy type that medicine knows how to do is to put a gene copy inside of an AAV9 virus or similar and to administer this gene therapy directly into the brain, like the three CDD gene therapies in the “near now” category. Anything else, is still a blurry (but hopeful) future.

4. What’s good enough and the big head problem

One thing that became clear in the discussions with the speakers and the industry panel is that because AAV gene therapies can only be done once, we really need to be sure that we got the right dose and distribution before trials. In other diseases where the main “gene therapy” type is an Antisense Oligonucleotide (ASO), which is like a piece of DNA that you inject into the spine once every few months, you can go to trials earlier and figure out the right dose there, but you cannot do this in viral-delivered therapies which are once-and-done. I will give you two real examples for this go-to-trials speed advantage with ASOs: (1) in Angelman, Ultragenyx went into the clinic initially with a dose of ASO too high, they saw some localized inflammation in the spine and scary leg paralysis but that was transient, and they could continue dosing those same patients with lower doses. (2) In Dravet syndrome, Stoke Therapeutics started trials thinking that the good dose would be 30mg, it wasn’t, so they went up to 45mg to try to see efficacy and still wasn’t enough, so then they started using 70mg as the dose and finally got impressive efficacy. In these two cases, the first dose was “wrong”, but it wasn’t a big problem because you keep dosing ASOs every few months so you can always go up or go down. But in CDD we haven’t had good shots on goal until recently to use ASOs, and we are instead using viral-delivered gene therapies as our first gene therapies, and because in those you literally only get one shot we are taking much longer to start trials because they have to be right from the start.

So how do we know when it is good enough? In the case of CDD the main challenge seems to be being confident that we are reaching enough neurons, because mice have small brains that are easy to cover with the virus but we have much much larger brains (a 5 year old has a brain 2,500-times larger than a mouse brain). So that is our challenge, to have so much virus spread throughout the brain in pigs and monkeys (mid-size brain) that we can trust we can jump to humans and get enough brain infection to see good efficacy.

There was quite a bit of debate about “what is good enough” to take those gene therapies to trials, which the consensus answer being that we need to be “comfortably sure” before starting trials. It still looks like it will come in the near future, but this is why it is so hard to pin-point exactly when. And the feedback from the industry experts in the panel was that even though we know the future will bring better gene therapies than the current most-advanced ones, this should not prevents us from starting trials with the almost-ready ones as soon as they are ready. Because patients don’t have so much time to wait in particular if they are young, and because we don’t know what future technologies will bring us and when.

As I write this, I am also thinking that we need to work hard on getting non-viral therapies to move to trials because they can be combined with the viral gene therapies, while scientists have not yet found a way to be able to give more than one viral gene therapy to the same person (the “redosing” problem, see also the next section). There are projects that were not presented at the Forum because they are early stage but they fit this need very well, such as the development of ASOs to increase CDKL2, ASOs to fix CDKL5, and making the CDKL5 enzyme in the lab to then infuse it into the brain (enzyme replacement therapy). I hope we can review these next year.

5. How the patient community can help

Industry panel, from left to right: Ralf Schmid (Novartis), Sharyl Fyffe-Maricich (Ultragenyx), Randall Kaye (Longboard), Brian Moseley (UCB) and moderator Majid Jafar (Loulou Foundation)

We had a panel with industry experts in drug and gene therapy development to see how we, the community, can help get new treatments forward faster. Some messages were:

• EDUCATE/RESEARCH: Help families understand that being part of research should be part of the treatment paradigm. It doesn’t need to be get into clinical trials with drugs, but perhaps observational clinical studies like CANDID, or biomarker studies like ELPIS. If patients don’t participate then we can’t get that next generation of treatments.

• RESEARCH: Help validate scales and outcome measures that can go beyond seizures, so that the new therapies can show that they are better than the current seizure therapies (I think we are already doing this well with the U01 and the CANDID studies and with ELPIS)

• EDUCATE families about gene therapies: what can we realistically expect, what does the journey of a trial for a gene therapy looks like…

• ADVOCACY: Some challenges that we can’t fix but can perhaps influence are getting regulators to understand what we need for gene therapy clinical trials, and also the problem of pricing for gene therapies.

• RESEARCH: also beyond our reach but where we can join researchers and other communities, is the problem of figuring out a way to make gene therapies redosable. If we know that we have a second-shot, and it is not only a one-shot goal, it will make it easier for people to participate in trials and for companies to run those trials. One way that we could help this is for example to have a focused workshop or session at the next Forum about the immune side of gene therapy and how to be able to one day re-dose patients.

I will add two things that they didn’t say but that I think are important roles that the community also plays towards getting new treatments:

• RESEARCH/ COMMUNITY: I noticed that several of the presentations were on research projects that had initially been seeded by some of the national patient groups, like Canada, Italy and Spain. So this goes to show that seeding research is another important role of the patient community that can start the building of a mountain with the first grain of sand. I think this is a very important function of patient groups also, to seed CDD research in their countries.

• COMMUNITY: We really need to find more patients. It is clear that there are more patients living with CDD that don’t know their diagnoses yet, than those who already have the correct diagnosis. An undiagnosed patient is a person who might be in the wrong treatment, who will miss all these trials, and who can’t help us solve the science questions (including the accurate epidemiology of the disease). I believe this needs to be addressed at a country level so I am adding it to our to-do lists!

6. The patient community: belonging, believing, and getting work done

The Forum traditionally opens and closes with the voice of the patient, and this year opened with Lily Howard telling us her experience as a sister to Harper, a little girl with CDD. Lily spoke about isolation and forced maturity, and feeling different from other kids and not able to connect. That’s why she has created an event for siblings, so that they get to create a sense of belonging.

Image: Majid and Lynn Jafar (Loulou Foundation, parents to Loulou); Lily Howard (Hope-4-Harper, sister to Harper); Andreas and Ana Born (CURE5; parents to Siena); and Heike Knip (CDKL5 Alliance President, dad to Valentina)

During the big gala dinner night, the patient award went to Ana Carolina and Andreas Borg, the parents of little Siena, who talked about the initial shock of the diagnosis, discovering a world that they didn’t know existed, to then finding purpose and a sense of agency in advocacy. I will share one beautiful sentence from Andreas: “all solvable problems can be solved if enough talented people put their energy into them”, and one from Ana: “we always look for heroes, and I’m proud I’m raising mine”. That’s the magic night of the Forum where we all end up crying and at the same time believing in a wonderful future that we can build.

To close the Forum, the outgoing Chair of the CDKL5 Alliance, Heike, spoke once again about the need for Unity in the patient community and shared the highlights from the last year work by each patient group in the Alliance. He also reminded us that we should try to improve quality of life, not just focus on gene therapies, with the example for how his daughter Valentina has gone from having 3-4 seizures a day to having 3-4 seizures a week in one clinical trial, so every bit that we can do helps a lot. This call echoes the words from Lily at the opening of the Forum, when she told us that even assistive technologies (not even medicines) can improve quality of lives for patients and their families. It is a beautiful reminder that at the end of the day, we are treating a person, not just a gene.

Last, Majid Jafar, co-Founder of the Loulou Foundation, wrapped up the Forum asking us all to meet at the CDKL5 Alliance meeting in Rome in June 2025, and announcing that the next CDKL5 Forum will return to Boston in October 27-28 of 2025. And he left us with a call to action: “we’ve come so far… and there is still so much to do. Let’s get it done”.

So we get back to work with our heads full of ideas and our hearts full of friends. I look forward to seeing you all in Rome and in Boston next year.

Ana Mingorance, PhD

Disclaimer: This is my own summary and key learnings, and not an official text about the Forum by the Loulou Foundation. I write these texts with the parents of people with CDD in mind, so excuse also my lack of technical accuracy in parts.

REPASO DEL FORO CDKL5 2024

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Hace ya diez años que la Fundación Loulou organiza una reunión anual, el Foro CDKL5, donde los científicos de academia y de industria trabajando en el síndrome de deficiencia en CDKL5 (CDD), junto con representantes de los grupos de pacientes, se reúnen para compartir las últimas novedades y avanzar hacia tratamientos y una cura. Tenéis el resumen de los años pasados aquí: 2018, 2019, 2020, 2021, 2022 and 2023.

La edición de 2024 tuvo lugar en Boston los días 28 y 29 de octubre, y volverá a Boston otra vez en 2025. Este ha sido el Foro más numeroso, con más de 200 participantes incluyendo representantes de 33 empresas y 18 grupos de pacientes. Esta fue también una edición especial porque marca el décimo Foro (hace 9 años del primer Foro). Así que voy a intentar resumir las conclusiones principales de la edición de este año, no incluyendo todas las presentaciones sino centrándome en los temas principales y los progresos que vimos, que son muchos. 

1. Seguimos aprendiendo sobre CDKL5 y sobre el síndrome por deficiencia

Imágenes: la investigadora Maria del Carmen Martin Carrascosa (CIPF), el Director de Foro Dan Lavery (from Loulou Foundation), y la medico e investigadora Josephine Thinwa (UTSouthwestern).

Sila Ultanir abrió una sesión dedicada a la biología de CDKL5 diciendo que hace unos años solo sabíamos que faltaba CDKL5, así que para tratar la enfermedad solo podríamos pensar en poner de vuelta ese CDKL5 pero ahora sabemos mucho más sobre lo que hace en las células, lo cual nos abre oportunidades para intentar corregir esas alteraciones directamente sin necesidad de devolver CDKL5, y nos da muchas más opciones.

Aprendimos de Oguz Kanca de Baylor que hay pacientes con mutaciones de ganancia de función en los genes CDKL1 y CDKL2 que también tienen síndromes de neurodesarrollo, con lo que CDKL5 no es el único gen importante de la familia. Y aprendimos de Maria del Carmen Martin Carrascosa del centro Pincipe Felipe en Valencia que las moscas de la fruta sin CDKL5 tienen epilepsia y estereotipias, con lo que parecen mejor modelo de CDD que los ratones. Y sin embargo en todos los animales que aparecieron en la evolución antes de que aparecieran las mandíbulas (si, las mandíbulas) usan CDKL5 casi como si fuera un CDKL1-4, que no hacen tantas funciones como nuestro CDKL5.

Uno de esos posibles genes CDKL redundantes es CDKL2, que ya el año pasado hablamos de que quizás podría ser una diana a modificar con terapias cuando nos falta CDKL5. Este año Kevin Dempster presentó lo que ocurre si a un ratón le quitas el CDKL5 y también el CDKL2. ¿Está peor aún ese ratón? La respuesta es que si, está peor, pero curiosamente CDKL2 solo hace algunas de las cosas que hace CDKL5, le faltan algunas funciones importantes como regular el canal de sodio Cav2.3 o los receptores de glutamato. Así que de cierta forma aumentar CDKL2 podría suplir alguna (pero no todas) de las funciones de CDKL5, pero aún tendríamos que corregir algunos elementos por separado por ejemplo aún necesitando inhibidores de Cav2.3 (os cuento más de esto más adelante en el texto).

Sobre la biología de la enfermedad, aprendimos de la experta en inmunología Josephine Thinwa que las personas con CDD podrían ser más sensibles a las infecciones víricas, que resultarían en una reacción inflamatoria más grande de lo normal, y de Lauren Orefice aprendimos que la falta de CDKL5 en las neuronas sensoriales es la responsable de que las personas con CDD tiendan a tener aversiones a ciertas texturas y roces (por tener la sensibilidad táctil alterada) y más propensos al dolor intestinal.

Otras presentaciones apuntaron a partes del cerebro importantes para el síndrome, como el tálamo, que Rachel Oren estudió como parte de la ceguera cortical (la señal del ojo llega bien hasta el tálamo y es en la conexión tálamo-cortical donde falla), o las neuronas GABAérgicas (las inhibitorias) que Tim Benke vio que eran responsables de la hiperexcitabilidad neuronal. Quizás por eso los fármacos que refuerzan la actividad de GABA como ganaxolona sean de lo mejor que hay para CDD.  

 2. Más que herramientas: el año de las plataformas

a. Células y ratones

Uno de los principales objetivos de la Fundación Loulou desde el principio es asegurarse de que cualquier científico en cualquier parte del mundo pueda investigar en CDD. Y eso ha implicado generar una colección de herramientas de investigación como anticuerpos para ver proteínas, y células pluripotentes de pacientes para convertirlas en neuronas en cultivo, y ratones con CDD. Y sobre todo hacer que sean de acceso abierto todas herramientas.

Y esto nos ha llevado a una colección importante de anticuerpos y células y ratones que están a disposición de la comunidad científica. Pero este año va un paso más allá y ha sido el año de las plataformas como servicio.

Imagen: diapo de la plataforma de evaluación de terapias en ratones con CDD; diapo de la plataforma de evaluación de fármacos en células derivadas de pacientes; y las investigadoras Liz Buttermore (BCH) y Jasmine Carter (Loulou Foundation) durante la sesión paralela sobre células iPS.

Quiero destacar las células iPS a partir de pacientes que se están usando como servicio en el Boston Children´s Hospital por Liz Buttermore, y la sesión de trabajo paralela que Liz y Jasmne Carter de la Fundación Loulou facilitaron durante el foro. Por cierto las células iPS son células pluripotentes que se hacen desprogramando células de la sangre o piel de personas (en este caso de pacientes) para que se puedan convertir en lo que queramos en laboratorio, y en este caso queremos neuronas, claro.  

En su charla, Liz nos explicó el trabajo de locos que ha sido conseguir hacer un modelo de epilepsia en placa de Petri usando las neuronas de pacientes porque estandarizar el protocolo de cultivo y de diferenciación en neuronas y su medición ha sido una odisea, pero al final es muy robusto y reproducible. Las empresas que están testando terapias para CDD ahora ya las pueden mandar a Boston para probarlas en este modelo de epilepsia en placa de Petri donde miden su actividad usando microelectrodos.

Y por la tarde tuvimos la sesión de trabajo con Liz y Jasmine Carter para ver como la comunidad académica y las empresas pueden trabajar de manera conjunta en desarrollar y utilizar estos modelos in vitro. Hubo debate sobre cómo aprender de los logros y errores de los demás, y crear algún canal de comunicación de grupo para poder hacerse preguntas porque es tan complicado trabajar con estas células. Me pareció una sesión fantástica y lo siento por las que ocurrieron en paralelo y que me tuve que perder.  

Y similar a lo que han hecho con estas células, los Laboratorios Jackson han creado un panel de diferentes modelos de ratón de enfermedades de neurodesarrollo que está también disponible para probar fármacos bajo un modelo de pago por servicio. Rajat Puri nos presentó datos de plataforma preclínica de prueba de eficacia en ratones con CDD donde consiguen unos fenotipos muy robustos en ratones de edades diferentes, lotes diferentes, e incluso testados por técnicos de laboratorio diferentes. De nuevo estos estándares suelen ser muy complicados y de ahí el valor de tenerlo disponible como servicio de pago en vez de tener que pasar por la odisea de adaptar el modelo en cada laboratorio. Los tests que más me gustaron son los que enseñan que los ratones con CDD son malísimos a la hora de enterrar bolitas en el serrín de su caja o de hacer nidos con papel para dormir, que serían el equivalente ratón a las actividades diarias que hacemos las personas en nuestro día a día.

¿y por qué es tan importante tener un servicio? Porque tener un ratón o una línea celular es como tener un ingrediente comprado en el supermercado, te lo tienes que llevar a tu laboratorio y cocinarlo, pero en el caso de estos servicios con células o ratones para medir eficacia de terapias son tan tan complicados que es fácil usarlos mal, así que tenerlos disponibles como servicios es como tener un restaurante donde puedes tener el plato ya hecho por muy complejo que sea. Y es más fácil ir a un restaurante a comer una paella que pasarse dos años aprendiendo a cocinar una decentemente.

b. Pacientes

Hay un estudio observacional en CDD llamado CANDID que mide la capacidad de diferentes escalas motoras, cognitivas y conductuales para capturar estos aspectos de CDD en pacientes, y para recoger datos que puedan en un futuro servir de grupo control en ensayos clínicos. Y es un estudio del que estoy muy orgullosa no solo porque fui parte del equipo original que lo ideó y diseñó sino porque se ha convertido en un estudio que la comunidad de pacientes ha adoptado. En el Foro, Xavier Liogier de la Fundación Loulou nos presentó los resultados con las escalas que ya han sido probadas en más de 100 pacientes en EEUU, Europa y oriente medio, y como no solo ya sabemos que escalas usar para ensayos, sino que resulta que hemos visto que si los ensayos clínicos siguen pidiendo un mínimo de 16 crisis epilépticas al mes, el 83% de los pacientes cualificarían para el ensayo. ¡¡83% es un porcentaje enorme!! En otros muchos síndromes suele ser menos de un 25% que cualifica, y como los ensayos clínicos suelen usar la epilepsia como su medida de eficacia principal eso nos hace un síndrome ideal para ensayos clínicos. ¡Esto es importante que se sepa!  

Imagen: Xavier Liogier (Fundación Loulou) presenta los resultados hasta ahora de CANDID, y un grupo de médicos y representantes de pacientes participan en una discusión sobre el estudio.

También hubo una reunión sobre el estudio CANDID donde Xavier y María Makarovskaya, los dos profesionales dela Fundación Loulou a cargo del estudio, preguntaron a los médicos y a los representantes de pacientes sobre su experiencia con el estudio hasta ahora y su input sobre posibles ajustes y cambios. Y es en ese momento cuando me di cuenta de que el estudio CANDID lo empezamos un grupo pequeño de personas pero ahora lo cuida un grupo muchísimo más grande de gente que incluye los 112 pacientes y sus familias y sus médicos y los neuropsicólogos del estudio y enfermeras… todos super involucrados en el éxito del estudio. Es una pasada, y una razón para que muchos estemos orgullosos.

También hay varios proyectos en torno a la obtención de biomarcadores en fluidos que se trató en otro de los grupos de trabajo paralelo. Un biomarcador en fluido es algo que se puede medir en sangre o líquido cefalorraquídeo o cualquier otro fluido corporal y que nos pueda indicar si una terapia está funcionando. Por ejemplo mirando glucosa en sangre tenemos un biomarcador de diabetes, y mirando colesterol sabemos cómo estás de salud cardiovascular. El italiano Maurizio Giustetto está mirando muestras de saliva para ver pequeñas vesículas que las neuronas liberan para hablarse las unas a las otra y que potencialmente podrían llegar hasta la saliva (esto es flipante). Y Massimiliano Bianchi lidera el estudio ELPIS que es una colaboración internacional donde miran en plasma (en sangre) cambios que indiquen lo que pasa en el cerebro. Ya el año pasado nos contaron cambios que se están viendo en sangre, y que hay con confirmar con una cohorte más grande de pacientes, y este año están expandiendo el estudio para incorporar más países y hospitales. También existe la posibilidad de recolectar muestras de sangre de pacientes y sus hermanos en el congreso de la Alianza CDKL5 del año que viene en Roma, así que estar atentos a más noticias sobre este proyecto.

3. Terapias: las de ahora, las de casi ahora y el futuro borroso

Al principio de la sesión sobre terapias, Omar Khwaja que es un médico que cuidaba de pacientes con enfermedades de desarrollo y luego se ha convertido en desarrollador de terapias, nos dio un resumen de las terapias en desarrollo para CDD.

Ahora mismo tenemos ganaxolona, aprobada en EEUU y en Europa aunque aun no disponible en Europa comercialmente, y muchas de las familias con CDD están tomando Epidiolex ya sea como Lennox-Gastaut ya sea como fuera de prescripción. Con lo que “casi” tenemos dos fármacos aprobados. Luego tenemos el ensayo clínico de fenfluramina que está terminando, el de bexicaserina a punto de empezar (para síndromes con epilepsia incluido CDD). Y tras esos tenemos un grupo de 4 terapias “casi listas” para ensayos, incluidas tres terapis génicas.

En palabras de Omar, hemos avanzado muchísimo en estos 9 años desde el primer Foro, con una colección de terapias en desarrollo incluidas terapias génicas en las últimas fases pre-clínicas y varios fármacos en ensayos o aprobados. Os animo a leer las entradas del Foro de años pasados para ver este progreso, que incluye programas que no avanzaron como ataluren que falló en Fase 2 y soticlestato que salió positivo en Fase 2 pero la empresa eligió no seguir hacia Fase 3.

a. Las de ahora

Imágenes: Sabine Bongardt de UCB Pharma, Randall Kaye de Longboard, y una diapo de la presentación de Elisa Borghi sobre el ensayo con el suplemento pre-biótico y post-biótico.

 UCB Pharma presentó el progreso con el ensayo de Fase 3 de fenfluramina, que posiblemente cierre reclutamiento al final de este año. Hicieron un llamamiento en especial para niños de entre 1 y 2 años de edad de los que esperan poder incluir una veintena en el ensayo. Esto es muy excepcional, la mayoría d ellos ensayos empiezan a partir de los 2 años, y en una enfermedad como CDD que debuta incluso en el primer mes de vida, esperar a los dos años puede implicar más de mil crisis epilépticas hasta poder tomar fenfluramina (o cualquier otro fármaco que generalmente solo está aprobado para usar a partir d ellos dos años). Así que si conocéis alguna familia con un niño o niña con CDD de esa edad decidles de este ensayo clínico para que puedan cerrar reclutamiento a final de año con suficientes casos de menos de dos años y permitir una aprobación desde esa edad.

Y mientras acabamos este ensayo empezamos otro. La empresa Longboard está desarrollando un fármaco llamado bexicaserina que es una fenfluramina de segunda generación, y que está a punto de empezar un ensayo de Fase 2 donde juntan todos los síndromes con epilepsia, con especial interés en los más comunes como CDD. Buscan pacientes de 2 a 65 años, con cuatro crisis contables al mes como mínimo, y planean abrir el ensayo en 80 hospitales, quizás más de 100, y empezar pronto. Así que preguntad a vuestro médico si están en contacto con Longboard para este ensayo clínico con bexicaserina llamado DEEp OCEAN.

Por cierto Lonboard ha ganado mucha popularidad recientemente, primero por la decisión de ir a por todos los síndromes juntos, y luego porque han sido comprados pro la empresa farmacéutica Lundbeck que es la que hace clobazam. Longboard recibió el premio Foro CDKL5 de 2024 a la “Empresa haciendo una diferencia” y su director médico Randall Kaye habló de interpretar un semáforo en ambar como una señal para acelerar (que dice que es lo que hace la gente en ciertas ciudades). Explicó que la idea de convencer a los reguladores de dejarles juntar todos los síndromes en un ensayo para que así el fármaco se apruebe para todos es algo complejo y amucha gente les daría que pensar y frenarían, como con un semáforo en ambar, pero que Longboard decidió ir a por el desafío y acelerar la posible aprobación de la primera terapia para todos los síndromes. Para nosotros este ensayo es otra oportunidad de acceder a un fármaco nuevo años antes de que esté disponible comercialmente.   

Y en el Foro tuvimos también una presentación muy interesante de Elisa Borghi sobre un ensayo que está empezando en Italia con un suplemente que mezcla pre-bióticos y post-bióticos, o sea “comida para las bacterias buenas” y “productos que liberan las bacterias buenas”. Este proyecto comenzó con financiación del grupo italiano de pacientes y ahora está en ensayo de Fase 2 para ver como mejoran la función intestinal y a epilepsia de los pacientes, que parecen estar relacionadas. Una cosa que me gusta de este estudio clínico es que si resulta positivo las familias pueden adquirir directamente el suplemento ya que no hace falta esperar a aprobaciones regulatorias y de precio que suelen tardar años en el caso de fármacos. Y teníamos otra compañía en el Foro, pero que vino sin presentar, que también está desarrollando una terapia dirigida a la microbiota intestinal pero usando bacterias de las buenas (o sea no es pre- ni post-biótico sino un tratamiento biológico). Yo espero que el año que viene si presenten y poder tener una sesión sobre las intervenciones clínicas para estudiar y tratar la interacción microbiota-cerebro.

b. Las de casi ahora

No se si sois conscientes de que ya tenemos cuatro programas incluidas tes terapias génicas pasadas la “nominación de candidato clínico”. Un candidato clínico es como llamamos en la industria a un fármaco o terapia que ya hemos terminado de diseñar y de optimizar y ya es final, con lo que lo pasamos a la etapa de estudio de toxidad en animales mayores que ratones para poder entonces pedir el permiso de usar en ensayos clínicos (la “IND” es ese permiso).

Imágenes arriba: Emil Kakkis de Ultragenyx y una diapo de su terapia génica. Diapo de Lario Therapeutics.

Imágenes  abajo: Diapo de la terpia de UCDavis y Kyle Fink de UCDavis; diapo sobre la terpia génica de la Fundación Loulou y Penn.  

Uno de esos es la terapia génica de Ultragenyx, que su CEO Emil Kakkis nos explicó que ya llega a suficientes neuronas en cerdos y que es segura, y esperan en unos meses decidir sobre posibles ajustes en la forma de administrarlo para ayudar a que llegue a más células antes de avanzar hacia ensayos. Emil también compartió los resultados que están obteniendo en su empresa en ensayos clínicos con otras tres enfermedades neurológicas y nos dejaba con la lección esperanzadora de que “el cerebro es más plástico y más hábil de lo que creemos”.

Un segundo programa en esta categoría de proyectos “casi ahora” es la terapia génica de la Fundación Loulou que desarrolla via su empresa subsidiaria Elaaj y que se está desarrollando en el Programa de Terapia Génica de UPenn bajo la dirección del super experto de terapias génicas Jim Wilson. Jim hace poco que ha dejado la universidad y se ha llevado el proyecto a una nueva empresa llamada Gemma Therapeutics, con lo que científico Janine Lamonica de Gemma presentó este proyecto. Esta terapia génica también tiene todo lo de toxicidad completo y con buenos resultados y es un candidato clínico que también está listo para avanzar hacia ensayos, aunque no dieron fechas.

Tanto la de Ultragenyx como la de Loulou son terapias génicas muy similares, consistentes en el gen human CDKL5 metido dentro de un virus adeno-asociado (AAV) y administradas mediante inyección directa en la cisterna magna que es el espacio lleno de líquido cefalorraquídeo que hay en la nuca.

Una tercera terapia génica que está ahora avanzando a experimentos de toxicología es la de reactivación del gen CDKL5 inactivo de Kyle Fink en UCDavis que usa una especie de CRISPR 2.0 para encontrar-y-activar en vez de encontrar-y-cortar que hacía el CRISPR original. Esta terapia va también dentro de virus AAV, en este caso dentro de dos porque el CRISPR 2.0 es muy grande (pero en una inyección hay millones de virus de cada uno de los dos tipos con lo que se juntan en las células). La terapia hace muy bien lo de encontrar el segundo CDKL5 que está inactivo en cada neuronas (solo leemos uno) y hacer que se lea de modo que todas las neuronas lean los dos, asegurando que todas las neuronas lean el bueno. Y sus experimentos en ratones son en ratones adultos donde funciona muy bien con lo que nos confirma que al menos en ratones nunca es demasiado tarde para restaurar la expresión de CDKL5 y ver mejoras clínicas (o preclínicas).

Y el cuarto proyecto que ha nominado un candidato clínico y que es un fármaco (no una terapia génica) es el de inhibidores de Cav2.3 de la empresa Lario. Hace dos años nos contaron que el canal de calcio Cav2.3 hace que disparen las neuronas glutamatérgicas (excitatorias) y que en general es controlado y frenado por CDKL5. Pero al faltar CDKL5 ese canal está demasiado activo y las neuronas excitatorias están descontroladas, por eso necesitamos inhibidores del canal. Hace un año nos dijeron que la empresa Lario estaba trabajando en inhibidores, y este año nos han enseñado una dosis-respuesta preciosa en neuronas de pacientes en la plataforma de epilepsia en placa de Petri de Boston. Dosis-respuesta significa que a más dosis más eficacia de corrección de la actividad descontrolada de esas neuronas de pacientes. Como esto es un fármaco y no una terapia génica tiene el atractivo de que se puede combinar más fácilmente con otros tratamientos.  

c. El futuro borroso

En esta categoría tenemos todas las otras terapias en desarrollo, incluida la edición genética (que arregla la letras que está mal, que está haciendo David Liu), o la terapia génica que arregla las mutaciones non-sense (de la empresa Tevard), o los proyectos en fase temprana de ASOs para aumentar CDKL2 o arreglar CDKL5, y también los de terapia de reemplazo enzimático que es hacer la proteína CDKL5 en el laboratorio y dar infusiones periódicas a los afectados. También hay programas que estamos considerando con terapia génica pero vía intravenosa, usando virus que pasan de sangre a cerebro. Todas estas avenidas se están explorando pero no sabemos ni SI llegarán ni CUANDO llegarán a ensayos clínicos, por eso lo del futuro borroso. Lo que sabemos es que hoy por hoy, lo que la medicina sabe hacer bien es poner una copia del gen dentro del virus AAV9 o parecidos y administrarlas directas al cerebro, como hacen las tres terapias que están cerca de ensayos clínicos. Todo lo demás es aún un futuro borroso aunque esperanzador.

4. A qué llamamos “suficientemente bueno” y el problema de la cabeza grande

Una cosa que quedó claro con los ponentes y el panel de expertos de industria es que como estas terapias que usan virus AAV solo se pueden dar una vez, hay que estar super seguro de que sabemos la mejor dosis y vía de administración antes de decidir empezar un ensayo. En otras enfermedades donde la terapia dirigida a la causa usa otra modalidad, por ejemplo los oligonucleótidos antisentido (ASOs) que son como cachitos de ADN que se dan por punción lumbar cada par de meses, se puede ir a ensayos más rápido porque se puede ajustar la dosis en la clínica, pero eso no se puede hacer con los virus porque solo se pueden usar una vez. Os voy a dar dos ejemplos de esa ventaja de los ASOs a la hora de ir a ensayos más rápido: (1) en el síndrome de Ängelman, Ultragenyx empezó ensayos con un ASO con una dosis que resultó ser muy alta lo que produjo una reacción inflamatoria en la médula espinal que resultó en parálisis temporal de piernas, pero pudieron continuar el ensayo incluso en esos mismos pacientes dando una dosis más baja. (2) en el síndrome de Dravet, la empresa Stoke pensó que la dosis de su ASO buena sería la de 30mg, y empezaron con esa pero no vieron mucha mejora, así que subieron a 45mg y vieron un poco más pero no suficiente, y por fin con la dosis de 70mg dieron en el clavo con una eficacia muy alta. En ambos casos, la primera dosis la eligieron “mal”, pero no fuer gran problema porque como el ASO se da cada par de meses pudieron subir o bajar la dosis como fuera necesario. Pero en CDD no hemos tenido hasta ahora una buena oportunidad de usar ASOs, y los proyectos dirigidos a la causa más avanzados que hay usan todos virus, y esos solo se pueden usar una vez, así que con una oportunidad única tenemos que estar super seguros de que la dosis es la correcta, y por eso estamos tardando más que otros síndromes en empezar ensayos.

¿Y como sabemos cuando una terapia es “suficientemente buena”? en el caso de CDD nuestro problema principal es estar convencidos de que llegamos a suficientes neuronas, porque los ratones tienen un cerebro chiquitito que es fácil llenarlo entero con el virus pero nosotros tenemos un cerebro mucho más grande (un niño de 5 años tiene un cerebro más de dos mil quinientas veces mayor que un ratón). Por eso el desafío es llegar a tener una distribución del virus suficientemente amplia en monos y cerdos que tienen cerebros más medianos que estemos seguros de que al saltar a humanos consigamos suficientes neuronas infectadas para obtener eficacia.

Y hubo bastante debate en el Foro sobre cómo sabremos que es “suficiente” para poder decidir empezar ensayos, y la respuesta consenso es que debemos estar bastante seguros antes de tomar la decisión. Y aún parece que lo conseguiremos en el futuro cercano, pero por eso es tan difícil saber cuándo exactamente. Y el consejo de los expertos de industria es que en cualquier caso, aunque sepamos que el futuro nos traerá terapias mejores, eso no debe frenarlos a la hora de avanzar algunas de las del “casi ahora” a ensayos en cuanto estemos bastante seguros de que las sabemos usar lo mejor que podemos. Porque por un lado no podemos esperar para siempre, las personas con CDD no deben esperar muchos años sobretodo si son niños, y por otro lado porque la verdad es que no sabemos cómo de buenas serán esas terapias futuras ni cuando llegarán.

Y mientras escribo esto estoy pensando que por eso necesitamos meter más caña al desarrollo de las terapias dirigidas a la causa que no usan virus, como la hacer la proteína en laboratorio (de reemplazo enzimático) o los ASOs, porque los científicos no sabemos aún como dar una segunda dosis de virus a una persona que ya ha recibido una terapia génica con virus pero esas otras si son combinables. Así que espero el año que viene en el Foro oír de los progresos con esas terapias no víricas.

5. Cómo puede ayudar la comunidad de pacientes

Panel de expertos, de izquiera a derecha: Ralf Schmid (Novartis), Sharyl Fyffe-Maricich (Ultragenyx), Randall Kaye (Longboard), Brian Moseley (UCB) y el moderador Majid Jafar (Fundación Loulou)

Tuvimos un panel con expertos en desarrollo de fármacos y terapias génicas de industria para hablar de cómo desde la comunidad de pacientes podemos ayudar a acelerar el desarrollo de tratamientos. Algunos de sus mensajes fueron:

• EDUCACIÓN/INVESTIGACIÓN: Ayudar a las familias a entender que participar en algún proyecto de investigación debería formar parte de lo normal para familias, por ser una enfermedad rara. No tiene por qué ser un ensayo clínico con fármacos, sino los estudios observacionales como CANDID o de biomarcadores como ELPIS. Si los pacientes no participan no podremos sacar ademánte la nueva generación de tratamientos.  

• INVESTIGACIÓN: Ayudar a validar escalas cognitivas, motoras y comportamentales para poder documentar en ensayos clínicos la eficacia de los tratamientos que no son anti-epilépticos (yo creo que esto ya lo hacemos bien con todos los estudios que hay en marcha).

• EDUCACIÓN a familias sobre terapias génicas: qué se puede esperar realísticamente de una terapia de este tipo, cual es el proceso de participar en un ensayo clínico con una terapia génica…

• POLÍTICA: hay desafíos que no podemos arreglar nosotros, pero que podemos influenciar, como es ayudar a que las agencias reguladoras entiendan la necesidad y el valor de una terapia génica para CDD, y también el problema de precios de terapias génicas.

• INVESTIGACIÓN: También algo fuera de nuestro control pero donde podemos apoyar a investigadores y unir fuerzas con otras enfermedades es el tema de ver cómo hacer que las terapias génicas con virus se puedan dar más de una vez. Si supiéramos que hay una segunda oportunidad y no solo una, haría más fácil la participación en ensayos y también a las empresas hacer esos ensayos. Una forma en la que podemos ayudar en este campo es por ejemplo teniendo una sesión centrada en la respuesta inmunológica a la terapia génica en el próximo Foro, y en cómo poder evitarla para poder dar la terapia más de una vez.

Y quiero añadir dos áreas donde los grupos de pacientes pueden aportar mucho pero que no fueron mencionadas en el panel:

• INVESTIGACIÓN / COMUNIDAD: En el Foro vimos que varias de las ponencias eran sobre proyectos de investigación que fueron empezados con fondos de los grupos de pacientes de ese país, como Canadá, Italia y España. Y eso nos demuestra que financiar aunque sea con poco la investigación es otro papel importante de los grupos de pacientes, que con el primer grano de arena comienzan la creación de una montaña. Por eso creo que aportar esos primeros granos de arena a que se investigue CDD en sus países es una labor importante de los grupos de pacientes.

• COMUNIDAD: Necesitamos encontrar más pacientes. Está claro que hay más gente con CDD sin diagnóstico que con diagnóstico, y cada paciente sin diagnóstico es una persona que podría estar en el tratamiento equivocado, que no puede entrar en esos ensayos, y que no puede ayudarnos a responder todas estas dudas clínicas como la epidemiología verdadera del síndrome. Y creo que esto es un problema que hay que atacar país por país porque las barreras al diagnóstico son únicas de cada sitio, ¡así que nos lo pongo en la lista de tareas!

 6. La voz de los pacientes: comunidad, esperanza, y manos a la obra

El Foro tradicionalmente lo abre y lo cierra una ponencia de familiares, y este año lo abrió Lily Howard que es la hermana de Harper y nos habló de su experiencia como hermana. Nos habló de la soledad, y de la madurez forzada, y de sentirse distinta a los otros niños e incapaz de conectar con ellos. Por eso Lily ha empezado un evento para hermanos donde puedan crear entre ellos la sensación de comunidad y pertenencia que les falta en su ambiente familiar y escolar.

Imagen: Majid y Lynn Jafar (Fundación Loulou, padres de Loulou); Lily Howard (Hope-4-Harper, hermana Harper); Andreas y Ana Born (CURE5; padres de Siena); y Heike Knip (Presidente de la CDKL5 Alliance y padre de Valentina)

Durante la cena de gala, el premio a los pacientes fue para Ana Carolina y Andreas Borg, padres de Siena, que nos hablaron del shock inicial con el diagnóstico y de descubrir un mundo que no sabían que existe, y de cómo encontraron su lucha por conseguir tratamientos para CDD tanto un propósito de vida como una sensación de tener agencia. Os comparto una frase de Andreas: “Todos los problemas solucionables tienen solución si suficiente gente con talento pone su energía en resolverlos” y una de Ana: “todos necesitamos un héroe, y yo estoy orgullosa de estar criando el mío”. Esta es la noche del congreso en el que todos acabamos llorando y confiando en que podemos construir un futuro mejor.  

La última ponencia del Foro fue del actual presidente de la Alianza, Heike, quien nos habló de nuevo de la necesidad de estar unidos en la comunidad de pacienes y nos hizo un resumen de los logros de cada grupo nacional de pacientes de la alianza en este último año. También nos recordó que debemos buscar mejorar la calidad de vida de las familias, no solo centrarnos en la terapia génica, y nos daba el ejemplo de cómo su hija ha pasado de tener 3 o 4 crisis al día a tener 3 o 4 crisis a la semana en su últimos ensayo clínico, y cómo pada pequeña mejora ayuda muchísimo. Esto recuerda a cómo Lily nos dijo también en su ponencia de apertura que incluso las tecnologías de asistencia (de apoyo) pueden mejorar mucho la vida de los afectados y sus familias, no solo las terapias médicas. En ambos casos el mensaje es que no nos olvidemos de que estamos intentando ayudar a personas, no a genes.

Por último, Majid Jafar que es co-Fundador de la Fundación Loulou, daba broche final al Foro convocándonos a vernos en Roma en Junio de 2025 en la reunión de la Alianza y anunciando que el próximo Foro vuelve a Boston los días 27 y 28 de Octubre de 2025. Y nos dejó con una llamada a la acción: “hemos llegado muy lejos, pero nos queda mucho camino por recorrer. Manos a la obra”

Así que nos volvemos al trabajo con la cabeza llena de ideas y el corazón lleno de amigos. Os veo en Roma y en Boston el año que viene.

Ana Mingorance, PhD

Nota: este texto captura mis impresiones de las presentaciones del Foro que más me interesaron, no es un texto oficial del congreso emitido por la Fundación Loulou. Escribo estos resúmenes para los padres de personas con CDD, así que a veces me tomo ciertas licencias a la hora de explicar las partes mas técnicas.

DRAVET SYNDROME AND HOW WE CAN TREAT A HAPLOINSUFFICIENCY

I have heard some confusion around patients with Dravet syndrome who have missense mutations in SCN1A: are they candidate for the genetic therapies currently in trials or are they excluded from the trials?

The short answer is “Patients with Dravet syndrome caused by missense mutations in SCN1A are candidates for the clinical trials with ASOs and gene therapies to increase SCN1A expression, and will be candidate for this therapies after approval”. The rest of this entry is the longer answer.

What is a haploinsufficiency

If you have a child with Dravet syndrome with a mutation in SCN1A, as most cases have, you might have heard the word “haploinsufficiency”. Haplo means “single” in greek, as opposed to couple or two, so haplo-insufficiency applied to genetics means that they have insufficient copies of that gene because they have a single one, as opposed to two functional copies which is the default for most genes.

In the case of Dravet syndrome caused by mutations in SCN1A, the person has one good gene copy and one bad copy (due to mutations), which leads to no functional protein being produced from that back copy. That leaves them with 50% of the number of good sodium channels Nav1.1 that their neurons need. They have only half of what is sufficient.

The reason I am writing this entry is that we often describe Dravet syndrome as a protein haploinsufficiency, as if patients only had 50% of the sodium channels. But this is a simplification that can worry families of patients with missense mutations who actually have 100% of the sodium channels…. But half of those don´t work.

We also often use mouse models for the disease where indeed only 50% of protein is produced because they have one good copy of SCN1A and one copy that makes no protein. So we think that this is what always happens, they produce only half of the numbers of sodium channels that they need. The consequence, by the way, is less sodium then running through the neuron membrane and less neuron firing. And it is very intuitive to understand that the gene therapies and other genetic treatments will try to bring expression “back to 100%” to help neurons function well.

We often explain Dravet syndrome as only having 50% of the Nav1.1 sodium channels

But what about missense mutations then?

There are many patients with Dravet syndrome that have a mutation of a type called “missense”, the one that doesn’t break the gene, but instead gives you a mistake in the sequence for the sodium channel protein, so that it will have one wrong letter. So you still probably produce 100% of the sodium channels, but only half of them works. The consequence is exactly the same as if the non-functional channels were not even there, it results in less sodium running through the neuron membrane and less neuron firing. But families and even some scientists worry that these patients cannot get the genetic treatments that increase expression of the gene because it will increase both the good and the bad copies. But it doesn’t matter in Dravet syndrome. The bad copies are not “bad” as in doing something bad, they are just useless. In science we call them “loss of function”, they really don’t work, they have lost their function.

I call these cases “functional haploinsufficiencies”. Yes they still produce channels from the bad copy, but these are no longer functional, so when it comes to functional sodium channels they still have half of the ones they needed.

I always understand better if it is in visual form. So I will adapt one of my old cartoons where I pictured the sodium channel as a door in the membrane that lets sodium come in. I am also guilty of only drawing the 50% of protein being produced scenario, which is true for mutations that break the gene and make no protein. But I never draw the missense scenario, where the number of doors for sodium is still fine but half of them are closed. The result is functionally the same: the neuron only has half of the doors that it needs to get enough sodium in. It doesn’t matter if the other half of the doors are missing or closed. It really doesn’t matter.

Missense mutations still result in only half of the sodium channels (the sodium doors) being functional

For me the door visual makes it much easier to understand why the different types of mutation result in the same biological protein. It is like everyone trying to leave a concert at once and having only half of the doors that could handle that many people. It doesn’t matter if the other half of the doors don’t exit or are shut, the result is the same, not enough usable doors.

By the way years ago we made a Dravet mouse model with a missense mutation that has been seen in several patients. And we then looked at what happened to that channel: it is produce and nicely sits in the neuron membrane as it should, but it remains closed at voltages where the good channels open to let sodium in. In door terms, there is no problem in the number of doors, the mutant ones are just closed all the time, and therefore as useless as if they were missing.

Why is this important for clinical trials?

There are currently two therapies in clinical trials for Dravet syndrome that are designed to increase expression of the sodium channel Nav1.1 by increasing the production of protein (the channel) from the SCN1A gene.

The most advanced therapy does this by using a small piece of RNA called an “antisense oligonucleotide” or ASO for short. It is the drug zorevunersen from Stoke Therapeutics (also known as STK-001). The second one is a gene therapy that uses a virus to bring to neurons the instructions to read the SCN1A gene more. It is called ETX101, from Encoded Therapeutics. I won’t get into the science details, you just need to know that both are currently in clinical trials for patients with Dravet syndrome caused by mutations in SCN1A, and both work by ending up in an increase of good sodium channels (opened doors at the concert).

Both clinical trials accept patients with the two types of loss of function mutations in SCN1A, including the missense. They are not only for patients that have mutations that break the SCN1A gene (nonsense, frameshift, gene deletions). That is a misunderstanding that worries families and the reason for this post.

• ETX101 trials asks for “Participant must have a predicted loss of function pathogenic or likely pathogenic SCN1A variant.”

• Zorevunersen trials asks for “Documented pathogenic, likely pathogenic variant, or variant of uncertain significance in the SCN1A gene associated with DS”. By the way this trial is not currently enrolling, they finished their Phase 2 trials and are preparing for the Phase 3.

Also VERY important, the large Phase 1/2 trial with zorevunersen is completed, showed safety and efficacy in the patients treated with the genetic drug, and the company has publicly explained that even though they don’t have enough patients to mathematically compare missense versus the other mutations, there doesn’t seem to be any signal that the missense patients don’t respond to this treatment. In this trial they had 45% of patients with missense mutations, and 55% with truncating mutations which are the ones that make no protein from that gene copy.

So it is not true that clinical trials to upregulate expression of SCN1A are only for patients with truncation mutations. But what about safety?

Another worry by scientists has been that the brain won’t handle having 200% of sodium channels (of doors), that it will be dangerous. But the science to support this belief is not there, and in fact both companies had to evaluate their genetic therapies in healthy non-human primates (monkeys) who don’t have Dravet syndrome and therefore have their two GOOD copies of SCN1A, and to show that their therapies increase the production of sodium channels and the monkeys are still fine. Companies need to prove this before getting permission to run trials in patients. So monkeys are fine with 150-200% or more of open doors (letting more sodium in!), which means that we don’t have worries for patients going from 50% of open doors to hopefully 100% of open doors. The extra closed doors, if they have missense mutations of the type that results in protein being made but not functional, are really not a problem.

Gene therapies and ASOs that increase expression from the SCN1A gene or mRNA are also in trials for patients with missense mutations in SCN1A

IN CONCLUSSION

Patients with Dravet syndrome caused by missense mutations in SCN1A are candidates for the clinical trials with ASOs and gene therapies to increase SCN1A expression, and will be candidate for this therapies after approval.

What I learnt at the SYNGAP Conference 2023

Last year I attended the Syngap Conference organized by the SynGAP Research Fund the day before the American Epilepsy Society (AES) meeting. It was fantastic, but I did not write a separate summary for it, only a mention as part of my AES summary. But then this year I attended again the Syngap Conference, again the day before AES 2023 started, and I believe it deserves a separate summary. So here it goes: these are my main learnings from the 2023 Syngap Conference about the SYNGAP research and therapeutic field.

1 – COOL AND SCARY NEW BIOLOGY

There was a lot about the biology of the SYNGAP1 gene and the SynGAP protein at the conference. The main learnings that stayed with me are two:

Did you know that SynGAP seems to control cytoskeleton (the cell skeleton) and in particular the primary cilia? This is like a special part of the neuron that looks like a short tail. This is interesting because I work very much in CDKL5 deficiency disorder (another neurodevelopmental syndrome with epilepsy) and CDKL5 is also doing the same things!! This whole “cilia connection” is very cool and also very puzzling. I don’t know what to do with this information, but it seems that proteins that evolved to control the cell skeleton and that special primary cilia might have also evolved to control synaptic remodeling and that is why we get neurodevelopmental syndromes with epilepsy when they are mutated. Helen Willsey from UCSF was such a great speaker! One of the highlights of the conference.

That was the cool new biology. The scary new biology is that we learnt that syngapians spend in REM sleep only half of the time that other people do. REM sleep is when we dream… so having SYNGAP steals the dreams of the kids, and this is very sad. The good news is that REM sleep could be a biomarker for these kids.

2 – HELP OUR KIDS NOW: DRUG REPURPOSING

There were several talks about drug repurposing, which means seeing if there could be already something sitting at the pharmacy shelf (perhaps even in the supplement shelves) that could help syngapians today. Repurposing is the search for faster treatments while investing in the long term disease-modifying treatments.

We learnt about a research program by Rarebase using patient-derived neurons to characterize some potential drugs that may help increase the mRNA of SYNGAP1 (remember that there is one good copy of the gene that we can use to get more protein), and one in fruit flies missing SYNGAP1. The mutant flies have small eyes looking disorganized, which serves a read out to look for drugs and supplements that could fix their problem and therefore compensate for lack of SYNGAP1. The researcher, Clement Chow, explained that they are finding many drugs that come up as positive and that have similar action, like many anti-inflammatory drugs, so the results are looking promising. And we also heard from Zach Grinspan who has been running a repurposing trial in SLC6A1 and STXBP1 with a drug called phenylbutyrate that will also be tested in SYNGAP. This talk opened a very interesting debate about this type of repurposing trial. For example: do we need a consensus to pick the winner compounds? How are we going to test the potential repurposing drugs if they are already available for example at CVS? Should we go through 6 months of paperwork just to have ethical approval and spend much money on trials or go ahead and try it individually? And how would we learn from those N-of-1 family-run studies?

Prof Ingrid Scheffer, who is one of the most famous doctors in the rare epilepsy space, insisted that the only way to know if something works (and is safe) is to run randomized controlled trials, and that the burden should be in the companies that own those drugs, not on the patient groups. This was a great debate!

3 – THERAPIES TOMORROW: HIGHWAY TO CURES

To cure a disease like SYNGAP we know very well what we need to do: help neurons make more SynGAP. I moderated this session with the message that “we have all of the ingredients that we need to fix SYNGAP”: we know the cause, we have one good copy of the gene to use, the disease is not degenerative, the animal models are good, and the animal models indicate that the disease is likely reversible. We are also talking about a relatively large rare disease, with a very strong patient community working on solving the right problems, and there are already several companies working on treatments.

We had a presentation from Praxis and one from Stoke, both working on ASOs to boost SynGAP production using the good gene copy.  In both cases, these companies have more advanced ASO programs for other epilepsy syndromes so we will get to use those learnings for SYNGAP. And we also had a presentation from Tevard, a company working on a gene therapy to help neurons skip premature stop-codons caused my non-sense mutations. Tevard is planning to run clinical trials with this gene therapy in a selection of genetic epilepsy syndromes including SYNGAP, and they are ready to start safety studies in non-human primates next year to then progress to clinical trials.

I also know that there are more therapies being developed to target the cause of the disease, and some of those companies where present in the room although they didn’t give a talk, so therapies are coming.

And to prepare the field for those therapies the community is running A LOT of clinical studies to know the natural history of the disease and possible outcome measures (scales) to use for trials. A LOT. This included a disease concept model, the Ciitizen study, and an excellent endpoint-enabling study at CHOP that is designed the same way that companies design their observational studies, this is top quality. Also a lot on biomarkers. What I wonder is how to integrate all these data. What is clear is that with so much work this is not a road to trials, but a highway to trials, in particular the trials for disease-targeted treatments (the cures).

4 – THE KEY CHALLENGE OF MISSENSE CAN’T WAIT

The disease that we often call SYNGAP for short happens when one of the two copies of the SYNGAP1 gene is mutated, and this mutation sometimes breaks the future protein (non-sense, frame-shift, truncation, deletions) but sometimes the mutation makes a protein that has one wrong letter. This is not trivial, and read this section until the end to know the mind-blowing implications. This means that many SYNGAP patients have a mutated protein instead of a missing protein. What if we can fix those? Maybe they just need a bit of help with folding. What if they stay around and don’t let the good proteins work? Then we need a strategy to remove them. This is why there are several programs trying to understand what happens to those mutated proteins, which are often unique to each patient with a missense mutation. This includes in silico modeling and also in vitro real experiments.

But the biggest implication is perhaps not for treatment, but for diagnostics. We learnt from Gemma Carvill that genetic labs often don’t know how to interpret these changes of letter, so patients receive a genetic report for “VUS” or Variant of Unknown Significance. With a VUS you cannot be diagnosed, because maybe the gene is totally fine (we all have some different letters here and there in our DNA that are harmless). In SYNGAP1 gene sequencing for patients with epilepsy, the large majority are VUS, like 80% or so, so they don’t get a diagnosis. The other 20% is split between benign (trivial) mutations, and pathogenic which are the real SYNGAP. But then Gemma and her colleagues train a computational model to predict if a missense is bad or trivial, they found out that about 22% of the VUS are likely pathogenic mutations. What this means is that if we could solve the meaning of the missense mutations, the diagnosed patient population with SYNGAP could multiply by 3 or so. This has mind-blowing implications, not only to grow the patient population but to then help those new patients access better treatments and clinical trials and a community of families like theirs.

No wonder this is such an important priority for the SynGAP Research Fund!

5 – ALL FOR ONE

A real team

I am used to seeing patient groups focused on one country or territory, even when they call themselves international. This is understandable. I am a Spanish scientist, so I often collaborate with the groups in Europe (proximity and shared regulatory framework) and in Latin America (shared language and culture). And what I love about the SynGAP Research Fund is that it integrates all those worlds. You could even see that in the logos in all the conference materials:

• SynGAP Research Fund

• SynGAP Research Fund EU

• Fondo de Investigación de SynGAP

And you could also see it around the room, because this group is very international. We had Mike and Aaron and Hans and Sidney and Lauren and others from the US, and Vicky and Martha and Carlos Caparrós and others from Latin America, and Katrien and Virginie and likely others from Europe. This is a true international team and this is exceptional and wornderful.

Get treatment for everyone

A message that was heard multiple times during the scientific program was the concern for all families living with a syngapian:

• The focus on repurposing was: how can we get these treatments to everyone?

• The focus on missense was: how can we find all those missing families so they are not left in the dark?

• The joint work of the different territories US/EU/LATAM is also about getting to everyone.

• Mike Ganglia closed the scientific conference with the words “what are all the people out there doing with their non-diagnosed syngapians?! We owe it to those parents”

A unique community

Clement Chow (the fruit fly scientist) explained that “Mike found us on Twitter, where all beautiful relationships start”, referring to Mike Graglia. And now Clement is working on finding repurposing candidates for SYNGAP!

My own path to get to know this community was similar. I was invited to give a talk in San Diego in 2018, and a SYNGAP dad reached out to me also through Twitter and asked me if I would like to meet his son with SYNGAP and his family while I was in town. That was Aaron, Jaxon’s dad, and it is a very good strategy to get scientists to get interested in a rare disease.

These two stories are an example of the proactivity of the SRF and the SYNGAP patient community, and other quotes that I wrote down during the 2023 conference also communicate this same message:

Tom Frazier, who is developing web-based measures of behavior and cognition: “This community volunteers for studies more than any other”.

Clement Chow: “[…]the strength of foundations leading the therapeutic discovery for rare diseases right now, and this foundational machine is best oiled than any other foundation that I have worked with, you should be proud of it”.

Then the following day was the Families Day with I believe more than 40 families attending and even using the opportunity to collect clinical data for some of the research studies. This community is exceptional and ready to partner and drive research forward.

 * * * * * *

I hope you enjoyed this summary. If you are a SYNGAP family member, try to join us next year in Los Angeles right before AES 2024, there is also a second day focused on families after the scientific day. And if you are a scientist or clinician, please also come to LA one day early. This disease has all of the ingredients that we need to fix it, and a unique community behind it. Please join.

PS: my summary from AES 2023 is HERE