AES 2022: genetic epilepsies reach escape velocity

PART 1 – ESCAPE VELOCITY

I often write a summary of the main lessons from the American Epilepsy Society meeting, but this year there was so so much about the rare epilepsy syndromes that I was not able to follow the main conference, there was barely enough time to follow all what was happening around the syndromes (which you also see referred to as Developmental and Epileptic Encephalopathies, or DEEs).

So I will focus my summary this year on the development of therapies for the rare epilepsy syndromes.

The conference started really strong, with the SYNGAP1 Conference the day before the main AES conference, where we learnt from Dr Jacquie French that for the first time, in 2022 we had more trials in rare epilepsies than in adult epilepsy. Even if people with rare diseases represent only about 20% of the total number of people with epilepsy, now they have the lion’s share of the trials. This is huge news!

And during the main AES meeting it was clear that indeed, much of the attention is currently on the rare epilepsies, with much of the agenda dedicated to genetic diagnostic, understanding how the adults with rare epilepsies look (so we can find them and develop treatments!), and much much research on the development of treatments. That’s why I believe that this year, with the milestone of having as many trials in syndromes as in regular epilepsy, we have crossed a line and likely reached escape velocity. Because it is not only about the two or three “famous” syndromes anymore, or about anti-seizure drugs being tested for the syndromes. We have crossed a different line.

At the other side of this line are treatments that target the cause of the monogenetic epilepsies. And those treatments look very different than classical anti-seizure drugs, and those trials also look different. We have crossed the line of developing treatments for symptoms, to developing treatments for the cause of the disease. And the line of focusing on a few syndromes only (those with the most patients), to seeing treatments in development for many more. That’s escape velocity.

PART 2 – TREATMENTS TO CORRECT THE CAUSE OF 8 SYNDROMES

Here are some of my highlights for eight of these monogenetic syndromes as an update to families. There are more diseases, don’t be discouraged if yours is not covered in this summary, I couldn’t do all of them.

SCN1A

Dravet syndrome is the (mostly) monogenetic syndrome that has received the most attention so far, and as a result the one with the most approved therapeutics. We saw many updates at AES about the approved drugs, and presentations about ongoing clinical trials with soticlestat (Phase 3) and EPX-100 (Phase 2). But I will focus on the treatments for the cause of the disease.

One of the most anticipated news of this congress were the early results from Stoke using an antisense oligonucleotide (ASO) called STK-001 to increase the good copy of the gene SCN1A. That’s because Dravet syndrome is a haploinsufficiency, which means that one copy of the gene is bad but one is good and can be exploited to produce enough protein from that one copy. That’s what Stoke is doing. After completing lower doses as part of the safety protocol for this type of therapy, Stoke has recently started administering higher doses to patients with Dravet syndrome and seen seizure frequency reduction and also improvements in non-seizure aspects of the disease. There is more information about this on their website. This is still the first small group of patients receiving enough dose to measure efficacy, and the results look very positive to me.

Another company using a similar antisense (ASO) approach, but directed to the SCN1A gene (not the RNA like Stoke), is CAMP4, that presented at AES how they are getting their antisense treatment ready for clinical trials (this is the antisense that OPKO was developing).

At the SYNGAP1 pre-meeting we saw a fantastic presentation from Tevard Bio about their approach to attack Dravet syndrome using different approaches all directed to the SCN1A RNA. And while Tevard still needs more time to get to clinical trials, Encoded Therapeutics is very close to starting trials with their gene therapy using a virus to increase SCN1A expression from the good gene copy, and presented at AES their work on finding good clinical scales to measure non-seizure symptoms of Dravet syndrome (the AES links are broken, so you will have to take my word for it). Encoded is preparing to start trials in very young children with Dravet syndrome (not yet started), and their gene therapy has the potential to change the developmental trajectory of these kids. The challenge is to get the right scales to capture that efficacy, so both them and Stoke have observational studies ongoing to validate those scales.

And Dravet syndrome also has at least two companies developing activators for the Nav1.1 channel, Lundbeck and Xenon. These are drugs, what scientists call small molecules, and not genetic therapies. From these two, Xenon has the most advanced program (another broken AES link that I cannot use), and I could see the Dravet syndrome space developing similar to SMA and have first an ASO approved, then a gene therapy, and finally a small molecule, all restoring sufficient levels of the sodium channel currents.   

Shout-out to Veronica Hood, Scientific Director of the Dravet Syndrome Foundation who gave a fantastic talk about the impact of the patient groups in Dravet syndrome with major roles as conveners, educators, funders of early research and resource curators.

SCN2A

SCN2A is another sodium channel very important for neuronal functioning, so important that mutations that cause too much activity produce one of these developmental and epileptic encephalopathies (I will call it SCN2A Gain-of-Function) and mutations that cause one copy to not function also produce a syndrome with epilepsy and cognitive and behavioral manifestations (I will call it SCN2A Loss-of-Function). That means scientists need to find ways to turn off the channel or the gene for the first group, and find ways to boost expression of the good copy for the second group.

The company Praxis is doing just that, and working at both approaches with different types of treatment modalities. The most advanced program is called PRAX-562 and is a drug (a small molecule) designed to inhibit only two channels: Nav1.2 (that is the one produced by SCN2A) and Nav1.6 (produced by SCN8A). This drug looks really promising for people who carry mutations in either one of these channels that causes the channel to work too much, so it is for the Gain-of-Function mutations. And Praxis is about to start clinical trials for these two syndromes after completing Phase 1 in healthy volunteers.   

What’s interesting is that Praxis also has a second program for people with SCN2A Gain-of-Function, and that is an ASO called PRAX-222 developed in collaboration with Ionis, and it is also getting ready to start clinical trials. So 2023 is going to be a very good year for SCN2A Gain-of-Function. And Praxis is also working on an ASO to do the opposite: increase SCN2A expression. This is a treatment for the SCN2A Loss-of-Function patents and it is still at earlier stages of development.

I will mention Praxis more times in this summary because they are working on more syndromes, and I want to highlight that this company has parents of kids with rare DEEs working with them as part of the team, and this is a very good sign. When we have scientists working within patient organizations, and patient advocates working within biotech/pharma companies, we can start breaking down many of the communication and cultural barriers between both worlds and developing better medicines.

SCN8A

SCN8A is the gene that encodes for another very important sodium channel, called Nav1.6. This is a channel that makes excitatory neurons fire, so the most common mutations are the Gain-of-Function type, that make those neurons way too active. What we need is clear: reduce the channel expression, or inhibit the channel activity.

This patient community has done a really good work at trial readiness, and we saw at least three therapeutic programs at AES (I might be missing some):

• The clinical trial from Praxis with the drug that blocks Nav1.2 and Nav1.6 that is about to start.

• A clinical trial with another drug, developed by Neurocrine and Xenon, that is only inhibiting Nav1.6. This one is already in clinical trials!

• An ASO that we saw in posters and that reduces SCN8A expression so that there is not too much channel. This one is still in animal studies.

I look forward to the conference on SCN2A and SCN8A next spring because it looks like we will have many news about clinical trials for these syndromes!

KCNQ2

And from sodium channels we move now to potassium channels. This gene is very famous in epilepsy, because if you have a very young baby, under one month of age, that starts having seizures, the most likely cause is mutations in this gene. What these kids need is openers for this potassium channel, activators.  

And there are two companies developing activators, one is Xenon, who are taking an older drug (ezogabine) that was taken off the market back into the market this time for KCNQ2 epilepsy. The drug is currently in Phase 3 studies, which means that if the trial is successful it will lead to an approval for KCNQ2. The second one is also an activator, from Knopp/Biohaven, that is currently in Phase 1 studies and will then move on to trials in patients with KCNQ2 epilepsy.

As with SCN8A, we have gone from not having trials to having even competing trials with drugs designed to correct the channel problem, either too much (Nav1.6) or too little (the potassium channel Kv7) activity. And I mainly look forward to seeing the potential benefit of these drugs past the very early years, once children with KCNQ2 mutations often stop having epilepsy but still have the developmental impacts that are due to the channel malfunction.

SYNGAP1

There is so so much going on for SYNGAP1 that I cannot summarize it all here. The pre-AES SYNGAP1 conference was fantastic, with many families in the room (and also all of the famous clinicians and many companies). There are iPSC models and mice and rats, I really liked the rat model and how it can be used to study drug response for seizures, sleep and cognition. They also have an idea of the SYNGAP1 isoform that is needed for gene therapies, and the “reversibility experiment” of putting SYNGAP1 back into adult mice has been done and it looks very positive. There is also a lot of work ongoing around patient data, like Ciitizen to see natural history, and an outcome measure for communication called ORCA being adapted to SYNGAP1 with funding from FDA. It’s all looking ready for therapies to be run through trials! There are two very strong SYNGAP1 foundations working to get trial ready and it shows.

And talking about therapies, there are several ASOs in development for SYNGAP1 and other modalities of gene therapies. What happens in this disease is the classical haploinsufficiency: one good copy of the gene, and one bad copy of the gene. That’s why the focus of these therapies is in promoting more expression from the good copy so that synapses can go back to working well again.

Praxis is working on an ASO to increase SYNGAP1. It is called PRAX-090 and in recent presentations Praxis says they hope to nominate a candidate in 2023. A “candidate” is when the company considers that their experimental drug or antisense is “good enough”, and at that point they stop tweaking it and start generating the animal safety data that is needed for trials, so it usually takes 1 to 1,5 years from the time of candidate nomination to starting trials.

Stoke Therapeutics, the company developing the ASO for Dravet syndrome (SCN1A) also has a program for SYNGAP1 using the very same approach, and they have partnered it with Acadia. And another company called CAMP4, that is also working on upregulating SCN1A for Dravet syndrome, presented at AES their early work towards also developing an ASO approach for SYNGAP1. And there are some additional academic and industry (Ionis) efforts to develop ASO treatments, so it is likely that SYNGAP1 families will get multiple options of clinical trials to increase protein levels, which should be a treatment for all the different symptoms of the disorder.

But antisense oligonucleotides are not the only approach to rescue SYNGAP1 expression. At the pre-AES conference we saw how Tevard is applying some of their gene therapies to increase expression from the SYNGAP1 RNA, and how scientists at Penn are using a CRISPR-like approach (called dCas9) to increase expression from the good gene copy. These are all very early stage efforts that are likely to reach clinical trials after the ASO treatments.

So you see, a lot going on, and not everything is presented at AES! And shout-out to Marta Dahiya, a clinician and SYNGAP1 mum who gave a very interesting talk during the main AES conference about digital natural history studies using platforms like the one from Invitae/Ciitizen.   

STXBP1

Like the one before, STXBP1 is also a synaptic protein that when mutated causes haploinsufficiency: one good copy of the gene, and one bad copy of the gene. And the main therapeutic strategy to target the cause of the disease is therefore to promote more expression, often by exploiting the good copy, so that synapses can go back to working well again.

At AES there were several presentations around documenting the natural history of the disease, and also on validating scales to be able to run trials that count more than just seizures. The patient organization is working on a very large natural history study designed to validate outcome measures, and has recently announced natural history efforts by the companies Capsida and Encoded Therapeutics. These are gene therapy companies, the ones that use a virus to deliver the therapy to the brain, so we can imagine that gene therapies for STXBP1 are being developed even if they haven’t yet been announced.  

There is also a known collaboration between the company Ionis and the Prosser lab to develop and ASO to restore STXBP1 expression, and at AES we also saw a presentation from the company Q-State about an antisense program to restore STXBP1 expression, which is still at early stages.   

So it looks to me like STXBP1 disorder, like SYNGAP1 and others, have multiple companies working unannounced on therapies to correct expression of their faulty gene and that by next year AES there will likely be many more projects that have been officially announced. I very much look forward to that!

PCDH19

This is an interesting gene, because it encodes for a protein that makes cells touch each other to connect. It is in the X chromosome, so in females half of the neurons express the good X chromosome and the other half the one with the mutated PCDH19. That means that they have two type of neurons, with only half expressing the cell touch protein, and that is a problem because for neurons to touch each other they need to have the same code: either they both have PCDH19 or they don’t. What doesn’t work is only some having it. That is why in males, that express their only X chromosome in all neurons, mutations in PCDH19 don’t cause disease, because all neurons express the same code: no PCDH19.  

There are at least two ASOs in development to make all neurons have the same cell touch code by eliminating expression of PCDH19 in all neurons in girls/women with PCDH19-Clustering Epilepsy. The first one is from Praxis, and is called PRAX-080 and as for SYNGAP1 the company has recently communicated that they hope to nominate a candidate in 2023 (the fully optimized ASO that then gets prepared to go to clinical trials). And the company Ionis is collaborating with the Parent lab to also develop an ASO that will achieve the same result: make female neurons like make neurons by knocking down PCDH19.

I like that for PCDH19 we have had clinical trials with small molecules (ganaxolone Phase 2) so we know for sure that seizures are countable and how a phase 2 trial could look. That helps de-risk the field for future trials, when companies will likely still count seizures as the main symptom for drug approval in addition to including scales to measure improvements in behavior and other domains – just as currently for Dravet syndrome.

CDKL5

CDKL5 Deficiency Disorder (CDD) is another DEE where the gene is in the X chromosome, but in this case the protein is a kinase and the problem is not that neurons don’t connect with different neurons, but that half of the neurons are missing the very important function of the protein CDKL5. The therapeutic goal is to put that protein back, with the added challenge that because only one CDKL5 copy is expressed in each neuron (only the good one or only the bad one) we cannot use many of the strategies used for haploinsufficiencies.  

I dedicated a recent update to CDD from the CDKL5 Forum 2022, so please see that link to read how the first gene therapy trials to bring a new copy of CDKL5 to the brain of people with CDD might start as early as next year. And 2022 was a good year for CDD, we had the first drug approved for the disease: ganaxolone (approved by FDA, pending EU approval). So this year we had a new player in the big AES exhibit, with the large stand for Marinus highlighting their data for ganaxolone in CDD and helping educate the medical community about this rare epilepsy that now has a treatment.

As for PCDH19 epilepsy, CDD has very clear epilepsy that has been used already in clinical trials as the main measure for efficacy and that will help de-risk the upcoming clinical trials with therapies directed to correcting the cause, which should improve seizures as well as non-seizure symptoms (which are so much harder to measure). And like for other syndromes, what was talked at AES was just the top of the iceberg, and there are many more treatments in development for the cause of the disease that were not presented at the main medical conference.  Check out the Forum update for that.

3 – IN CLOSING

If you are a rare disease parent you might have only read the section about your loved one’s disease gene. So I encourage you to do two things:

One, please remember that companies often don’t talk about their projects until they are close to trials, and not all present at AES, so what you read above is only a snippet of what’s going on in reality (iceberg!).

Two, whether you are a parent or a scientist, step back and look at all the syndromes and the global picture that emerges: I have only talked about the treatments in development to address the cause of the syndrome, not the symptom. Long gone are the times when there were no trials in the syndromes so we didn’t have good clinical evidence about anti-convulsant drug efficacy in them. And we are even closing chapter two, the one of cannabidiol and the other anti-convulsant drugs being tested and approved for syndromes, although their activity is not specific to the syndromes. What you are seeing here is different. You are seeing multitude of programs to block or open channels, to increase expression of good gene copies or reduce expression of bad ones, and several are already in clinical trials in patients. We are closing chapter two, and reading from chapter three… the one with treatments for the cause of the disease reaching clinical trials. And the speed at which this is happening, and how broadspread it is across different syndromes, is unstoppable. We have reached escape velocity.

 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 2022 CDKL5 FORUM

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For the past eight 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 the past few meetings here: 2018, 2019, 2020 and 2021.

The 2022 CDKL5 Forum edition took place November 7-8 in Boston, returning to a face-to-face format after two on-line editions during the pandemic. Being back in person made this year’s meeting even more special. It was also, in my opinion, the best CDKL5 Forum meeting so far. Our understanding of CDKL5 deficiency biology and the pace of therapy development have advanced significantly in the last few years, so I will summarize my main take-home messages from this year’s Forum below and contrast them to where we were the last time we saw each other in Boston in 2019.

1. THE YEAR CDD BECAME PART OF THE 5 PERCENT

We always hear the same line: “there are more than 7,000 rare diseases, and only 5% have a treatment approved”. That is a special club of rare diseases that have received so much attention and investment that a medicine was specifically tested and approved for that rare disease.

In 2022, CDD joined that club.

In 2022, ganaxolone received approval from the FDA for treating seizures in CDD, and we are expecting the EMA decision soon. When we met last time at the 2019 Forum, we announced that Marinus was on track to complete recruitment for their ongoing Phase 3 trial with ganaxolone in CDD. Since we met last time, Marinus completed a first-ever global clinical trial for CDD in the middle of a global pandemic, and ganaxolone is now available for patients in the US and hopefully soon in other countries. I’m amazed at the courage of the Marinus team to bet on this un-tested rare disease, and to fight thought the pandemic to bring the first therapy to the market for people living with CDD. They have made the path easier for everyone else to follow.

And yet the first drug approval for CDD is only one of the two biggest news of the year…

2. CDD GENE THERAPY IS COMING TO CLINICAL TRIALS

One of the biggest hopes of the CDD patient families is the arrival of gene therapies to clinical trials. In CDD, half of the neurons (in girls) or all of the neurons (in boys) don’t produce the protein CDKL5, which is a very important protein for brain functioning. Gene therapies aim to use a virus to carry a new copy of the CDKL5 gene to neurons, so that they can start producing the protein [see also the next section in this update].

At the 2022 CDKL5 Forum, Emil Kakkis, CEO of Ultragenyx, said the words that CDD families were waiting for: “Gene therapy for CDD is coming to the clinic, we believe next year”.

Later in the conference, Sharyl Fyffe-Maricich (who has been leading the CDD gene therapy program at Ultragenyx) explained all of the steps they have taken to optimize their gene therapy to that it could get to as many neurons as possible before sitting down with regulators to talk about starting a clinical trial. The quality of their science is impressive, and Emil explained that clinical development is hard but we will all be in this together.

When we met in person last time at the 2019 CDKL5 Forum we were starting to have some data of experimental gene therapies in mice. Major questions back then were whether these therapies would work well enough in animals to progress to clinical trials, and when that might happen. We now finally have an answer and a timeframe: if everything goes well, clinical trials with the first gene therapy for CDD could start as early as in 2023.

This was the second big news of the year, and the highlight of the 2022 CDKL5 Forum.

3. TACKLING CDKL5 DEFICIENCY FROM ALL ANGLES

During the Forum Dinner, Phil Reilly (a very experienced developer of medicines for rare diseases) shared with us some stories about diseases that used to be considered untreatable until patient families intervened and played a key role to developing a cure. His message was: “there is no intractable disease”.

The next day, Emil Kakkis would remind us that “CDD has reversible components, and that is not true for many other neurological diseases”. He was referring to what we know from mice with CDD, where multiple aspects of the disease are reversible in older animals if CDKL5 is re-expressed. We also know that CDD is not a degenerative disease or even a strict neurodevelopmental disease where CDKL5 is needed only during a limited time in development. It is actually a neuromaintenance disorder, as we saw in the 2020 Forum, so there is much clinical hope around the possibility of restoring CDKL5 expression in CDD patients.

At the 2022 Forum we saw many updates about different approaches to tackle CDKL5 deficiency from all angles. Here are some quick notes on the different approaches:

Treat the disease symptoms: there is a Phase 3 clinical trial ongoing in CDD with the drug fenfluramine. This drug has beautiful efficacy in Dravet syndrome, and the company that developed it (Zogenix) was recently acquired by UCB Pharma, one of the leading epilepsy companies. The clinical trial is already enrolling in the US and expanding to Europe and Japan.

Treat the disease symptoms: Takeda had evaluated the efficacy and safety of soticlestat in a small study in CDD and updated us about the patients that continued taking the drug after the study. From the 12 patients that participated in the small trial, 8 are still taking the drug and all have experienced seizure reduction during the time they’ve been taking soticlestat. And it is not just about seizures, parents reported overall improvements including in communication and engagement. I hope to see this drug considered for treating patients with CDD.

Correct the CDKL5 pathway: there is a new discovery that opens the door to designing new treatments to correct some of the direct consequences of CDKL5 being missing. I dedicate to it the entire section 4 of this update.

Add more CDKL5 protein: the development of an enzyme replacement therapy for CDD (make the protein in the lab and give it to patients) has proven to be very challenging. Maria Luisa Tutino presented at the Forum her work towards producing full-length functional CDKL5 to be used for enzyme replacement and all of the challenges that they are solving one by one. There is need for more labs and companies to join the efforts to develop an enzyme replacement therapy for CDD because it remains an important therapeutic approach and it is very hard.

Correct the mutated RNA: the CDKL5 gene gets copied into messenger RNA, which then is used to produce the CDKL5 protein. If a gene has a mutation, then that mutation is still copied into the RNA. There are a variety of strategies to try to make functional protein from a mutated RNA without needing to fix the gene. For example there is a project ongoing to develop antisense oligonucleotides (ASOs) that could help with mutations in CDKL5 that cause splicing problems (like spinraza for SMA) or also that could potentially skip exons that might contain a mutation (skip part of the RNA sequence, like some treatments for Duchenne). And we know that there are also companies developing approaches to help cells read past non-sense mutations, which is sometimes also the problem for some people with CDD, so I hope to hear more news about these approaches and see them tested for CDD.

Reactivate the second CDKL5 gene copy: we had two presentations at the 2022 Forum about gene therapies that use a version of CRISPR to find the inactive CDKL5 copy and reactivate it. Kyle Fink has been leading the development of one of these gene therapies for CDD for the last couple of years, and recently was awarded a $1,4M grant to further develop the gene therapy for CDD. He also received the Lab of the Year award at the Forum.

Fix the mutated gene: there are several new approaches in development for correcting letters in a gene, or inserting letters. Majid Jafar, co-founder of the Loulou Foundation, explained that Loulou is missing one letter in her CDKL5 gene, and that her mum had asked “why can’t they just put that letter back?” when learning about the diagnosis. David Liu has been advancing a modified CRISPR-like approach called prime editing to do precisely that: put one letter back. He showed us how he can already fix the CDKL5 of kids like Loulou in cells in culture, and he is now working at getting it to work in living mice. Some of these gene editing approaches are starting to make it to clinical trials barely 5 years after the technology was discovered. His ultimate goal is not just to be able to add or replace one letter, but to replace the entire mutated CDKL5 gene by a healthy copy. It is always inspiring and a window into the future to hear David give a talk.   

Add another copy of the CDKL5 gene: this is the classical gene therapy approach where scientists use a virus (usually AAV) to carry a gene to neurons. The virus cannot multiply, it just delivers the gene to neurons and from then on, neurons can produce the missing protein, in this case CDKL5. At the 2022 Forum we had a wonderful update about the Ultragenyx gene therapy program, and the news that it is progressing to clinical trials.

4. A BREAKTHROUGH IN UNDERSTANDING CDKL5

There were many presentations at the Forum about new understanding for how the CDKL5 protein works and some of the consequences to the brain when CDKL5 is missing. But I will only highlight one in this update, because I consider it a major breakthrough in our understanding of the protein and the disease. It also opens an important door to new treatments.

The discovery came from the lab of Sila Ultanir, at the Crick Institute. The protein CDKL5 is a “kinase”, which are proteins that can change the function of many other types of protein. This means that when the kinase is missing the problem multiplies because now you have all those other proteins not working well. The Ultanir lab has discovered a very important protein that needs CDKL5 to work properly, and it turns out to be a calcium channel (Cav2.3). When CDKL5 is missing, the calcium channel opens well but then closes too slowly, leading to too much calcium going through.

This is very important because many developmental and epileptic encephalopathies are caused by problems with ion channels, we call them “channelopathies” as a group. For example Dravet syndrome is caused by a sodium channel working less, KCNQ2 epilepsy is caused by a potassium channel working too much, and there is even a very rare syndrome caused by the Cav2.3 calcium channel working too much. The discovery that deficiency in CDKL5 makes that same calcium channel also work too much is unexpected and helps explain a lot.

I call this discovery a breakthrough for two main reasons:

1) We often wondered… if CDD is caused by a kinase missing, why does it look so similar to the channelopathies? Now we have the answer: CDD could be partly a channelopathy!

2) This discovery opens the door to designing new treatments to correct some of the direct consequences of CDKL5 being missing. Now we know that we want companies to develop Cav2.3 blockers.

 

5. MUCH PROGRESS EXPANDING THE RESEARCH TOOLBOX

For scientists to understand what CDKL5 does in cells, and to test treatments years before they are ready to go into trials, they need to model the disease in animals or cell cultures in the lab. There has been a giant effort by scientists across many countries to find animals or cells where we could remove CDKL5 and see a strong symptom (which scientists call “a phenotype”).

The most used animals in medical research are mice and rats. This year we had several great presentations that expand the CDKL5 research toolbox to fish and flies, and potentially frogs (tadpoles) and even pigs.

We had presentations from two groups showing that a tiny fish called zebrafish might help us research some of the symptoms of CDD. A group from Portugal has seen that zebrafish missing CDKL5 have bone problems (which also happens in patients!) and interesting motor symptoms that could be monitored to test experimental medicines in those fish. And a group from Boston is changing the fish genetics so that they can miss CDKL5 in only half of their neurons, which is what happens in girls with CDD.

My favorite presentations about new CDD models were two:

• The lab of Ibo Galindo, in Spain, has made fruit flies that lack the CDKL5 gene and they have very strong epilepsy and their disease is so severe that they even die sooner than normal flies with CDKL5. In fact flies only have one gene for CDKL1/2/3/4 and 5, so these flies are missing all of the CDKL genes! And they look like other good fly models of genetic epilepsies. The flies also have interesting behaviors, and could be a powerful genetic system to understand the function of the 5 human CDKL proteins by making the flies express each of the human genes and see which ones can make them healthy.

• The company Vyant is using stem cells taken from skin or blood samples from children with CDD to grow organoids in the lab. Organoids are like a ball of neurons and other brain cells all produced from the child stem cells and look like a mini-brain in a petri dish (they are to the right of the rat in the pictures that accompany this text). It turns out that organoids from kids with CDD have the in vitro equivalent of epilepsy. Vyant is using these organoids as a platform for drug screening directly in human cells, and they are already finding some promising compounds. I really liked their platform.     

I was very impressed with the tenacity of so many scientists making a giant effort to leave no stone unturned, and to check every animal and every cell and tweak them and optimize them. This means that today we have a variety of different models that can be used to answer different questions about biology and treatments, and this type of work takes a big community effort, it cannot be done by only a few labs. I’ll come back to this in the next section.  

6. “WE ARE IN THIS TOGETHER”

A theme that emerged as the 2022 CDKL5 Forum motto was “we are in this together”. We heard it in words, and we saw it in action. These are only some of the examples that we saw during the Forum:

• No patient left behind. There are patients with CDD in all countries, and that also means they come in all languages. Sadly language barriers are a major limitation to reach the international community. To bring together the data of as many patients as possible, and to be able to reach out to them about news such as clinical trials, the CDKL5 Registry is recently available in many of the common languages and will be expanding to more. Current languages are English, French, German, Italian, Spanish, Arabic, Chinese (traditional and simplified), Japanese and Russian! This was a lot of work, but we are in this together.

• Companies collaborating in clinical studies. When we met last time in Boston in 2019, we talked about the need for an observational study to validate outcome measures for CDD (to check that we know how to track CDD symptoms in a way that is useful for clinical trials). The catch is that we wanted only one study, with the different pharma and biotech companies coming together to co-design it and run it, so that we would not overburden the patient community. At the 2022 Forum, Xavier Liogier from the Loulou Foundation stood in that same stage to announce that the first patient has been enrolled in that study, called the CANDID study, which will have the size of a Phase 3 trial in CDD. The years in between came with much work (including getting the study reviewed by the FDA!) and also with a giant step from seven companies that came together in a study that is a first-of-a-kind precompetitive collaboration. We are in this together.

• Preclinical collaborations. The CDKL5 research community has always been exceptionally collaborative, and the Forum has a series of parallel workshops (the last two editions also added pre-meeting workshops) where we get organized. At the 2022 Forum we saw a proposal to get the companies developing treatments for CDD more actively involved in this preclinical collaboration network, because it is easy for pharma and biotech scientists to share advice, but hard to share actual research data! The goal is to have academics and companies compare their CDD mouse data to validate what are the best and most reliable endpoints (the best mouse symptoms). The academic groups are already doing this, and I hope that by next year’s Forum we can announce that companies are also joining this very needed effort. We are in this together.

• The patient alliance helps accelerate clinical studies. A big challenge for companies to run trials in rare diseases is to know how to find the right hospitals. The CDKL5 Alliance has put together a list of hospitals in the different Alliance countries where they have trusted clinicians. We learnt at the Forum that this resource has already helped accelerate the initiation of the observational CANDID study, and I hope that it will also help accelerate treatment trials. We are in this together.

• The leadership of patient families. The CDKL5 Forum is a scientific and medical conference, where we review the news from the previous year and get organized to help progress the field further. But it is also a meeting led by a patient family, where patient families feature prominently in the agenda and the discussions. We opened the meeting with the words from Natalie Ladly from CDKL5 Canada, sharing with the audience the toll of CDD on her family (#brynnstrong!). Simon and Fiona Walsh from CDKL5 Ireland also invited us to look into their family’s life during the Forum Dinner, and Rick Upp, from the IFCR, closed the meeting with an update from the CDKL5 patient community. The Champion of Progress CDKL5 Forum Award of this year went to Antonino Caridi, from CDKL5 Italy, one of the most loved and respected leaders from the patient community in the fight for a cure for CDD. And representatives from 14 different countries (the Alliance includes more than 30 countries!) were also in attendance, mixing with researchers and actively participating in the discussions, in particular during the interactive breakout sessions. That’s how the words and actions from the patient families during the Forum also spelled out how we are in this together.

SUMMARY

If we had to boil down the 2022 Forum to a few sentences, it would look like this:

There is no intractable disease.

CDD is now part of the 5% of rare diseases that has a treatment approved.

CDD gene therapy is coming to clinical trials.

And clinical development is hard, but we are in this together.

The Loulou Foundation started in 2015 with the mission to have “treatments for CDD (in clinical trials) by 2020, and cures by 2025”. Back then there were not therapeutic programs at all being developed for CDD, but there was faith in science and in the power of a large community. With the news shared at the 2022 Forum, it now seems realistic to believe that even before 2025 there will be people living with CDD who will have received a gene therapy as part of a clinical trial. This was a great year for CDKL5 research.  

I hope you enjoyed this summary. Please let me know your thoughts in the comments.

Ana Mingorance, PhD

Disclaimer: These are my own impressions from the presentations and topics that I was most interested in as a scientist and supporter of the patient community, 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 2022

Inglés / Français / Português/Brasileiro

Hace ya ocho 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.

La edición de 2022 tuvo lugar los días 7 y 8 de noviembre en Boston, volviendo al formato presencial tras dos años en formato virtual debido a la pandemia. Eso ha hecho el Foro de 2022 aún más especial. Para mi este ha sido el mejor Foro desde 2018 que fui al primero. Ha habido un progreso enorme en lo que sabemos de CDKL5 y la velocidad de progreso de las terapias, así que voy a resumir las principales noticias del Foro de 2022 y compararlas con cómo estaban las cosas la última vez que nos reunimos en persona, en 2019 también en Boston.

1. EL AÑO EN QUE NOS UNIMOS AL CLUB DEL 5 PORCIENTO

Seguro que habéis oído eso de “hay más de siete mil enfermedades raras, pero solo el 5% tiene algún tratamiento aprobado”. Es un club especial ese 5%, son las enfermedades raras que han recibido suficiente atención e inversión para que se haya desarrollado y llevado a ensayos clínicos un tratamiento específicamente para ellos.

En 2022, CDD se unió a ese club.

En 2022 ganaxolona se aprobó en Estados Unidos para tratar las crisis epilépticas en CDD, y estamos a esperas de las decisión de la agencia europea que se espera en cuestión de meses. Cuando nos vimos por última vez en Boston en 2019 hablábamos de que Marinus estaba cerca de completar el reclutamiento para su ensayo clínico de fase 3 con ganaxolona en CDD. Desde entonces Marinus completó el reclutamiento en un ensayo por primera vez global en CDD, en medio de una pandemia también global, y ya el fármaco está aprobado y disponible para los pacientes en Estados Unidos y esperamos que pronto en otros países. Hay que destacar la valentía del equipo de Marinus de apostar por una enfermedad que no tenía tratamientos previos, y de luchar a través de una pandemia para sacar a mercado la que sería la primera terapia para CDD. Han allanado el camino que ahora es más fácil para los que vienen detrás.

Y resulta que la aprobación del primer fármaco para CDD solo es una de las dos grandes noticias del año…  

2. LA TERAPIA GÉNICA PARA CDD AVANZA A ENSAYOS CLÍNICOS

Una de las mayores esperanzas para las familias CDKL5 es la llegada de las terapias génicas a ensayos clínicos. En CDD, a la mitad de las neuronas (en niñas) o a todas (en niños) les falta CDKL5 por tener un gen mutado. Y eso les impide producir la proteína CDKL5 que es muy importante para el funcionamiento neuronal. Las terapias génicas buscan usar un virus para llevar una nueva copia del gen CDKL5 a las neuronas, y que así puedan volver a producir la proteína [ver el repaso de estrategias de tratamiento en la sección siguiente].

En el Foro 2022, Emil Kakkis, que es el director ejecutivo de Ultragenyx, por fin dijo las palábras por las que llevábamos esperando los últimos años: “la terapia génica para CDD viene a ensayos clínicos, creemos que el año que viene”.

Más tarde vimos también la ponencia de Sharyl Fyffe-Maricich que es quien lidera el proyecto de la terapia génica de CDKL5 en Ultragenyx, y nos explicó todos los pasos que han tomado para asegurarse de que su terapia génica llega a tantas neuronas como sea posible antes de sentarse con la agencia reguladora a hablar de empezar ensayos clínicos. La calidad de la investigación que hace esta gente es impresionante, y Emil nos explicó que el desarrollo de una terapia a través de ensayos clínicos siempre es difícil pero que estamos juntos en todo esto.

La última vez que nos vimos en Boston en 2019 vimos la presentación de datos de terapias génicas en ratones con deficiencia en CDKL5, y en ese momento nos hacíamos aún dos preguntas muy importantes: si llegarían a funcionar suficientemente bien como para avanzar a ensayos clínicos, y cuando sería. Ahora por fin ya tenemos respuestas y fechas orientativas: si todo va bien, los primeros ensayos con la primera terapia génica para deficiencia CDKL5 podrían empezar en 2023.

Esta es la segunda de las grandes noticias del año, y sin duda el notición del Foro.

3. ATACANDO A CDKL5 POR TODOS LOS LADOS

Durante la cena de recepción del Foro, Phil Railly (un descubridor de terapias para enfermedades raras muy importante) nos compartía varias historias de enfermedades que se consideraban intratables hasta que padres de niños afectados tomaron cartas en el asunto y jugaron un papel clave para desarrollar curas. Su mensaje era que “no hay enfermedades intratables”.

Luego al día siguiente Emil Kakkis nos recordaba que “CDD tiene aspectos reversibles, y eso no pasa en muchas otras enfermedades neurológicas”. Hacía referencia a lo que hoy en día sabemos de que en ratones con deficiencia en CDKL5 la enfermedad es reversible, y también sabemos que no es una enfermedad degenerativa, ni siquiera de las típicas de neurodesarrollo donde la falta de la proteína durante etapas claves de desarrollo causa daños irreversibles. Hoy entendemos que la deficiencia en CDKL5 es un desorden de “mantenimiento de función neuronal”, como vimos en el Foro de 2020, con lo que hay mucha esperanza de cara a la posibilidad de devolver la expresión de CDKL5 a los pacientes con CDD.

En el Foro 2022 vimos actualizaciones sobre muchas aproximaciones terapéuticas para atacar a la deficiencia en CDKL5 por todos los lados. Os hago un resumen de lo que vimos:

• Tratar los síntomas: el ensayo con fenfluramina está en marcha y es el segundo ensayo de Fase 3 que tenemos en CDD. Fenfluramina ha tenido resultados muy buenos en el síndrome de Dravet, y la empresa que la desarrolla (Zogenix) ha sido comprada por una de las mayores empresas farmacéuticas líder en el campo de epilepsia, UCB Pharma. Los ensayos clínicos están reclutando en Estados Unidos y pendientes de arrancar en Europa y Japón.

• Tratar los síntomas: Takeda evaluó la eficacia y tolerabilidad de soticlestato en un estudio pequeño en CDD, y nos trajo una actualización de 8 de esos 12 niños que se quedaron tomando el fármaco tras terminar el ensayo. Todos han experimentado mejoría en el control de crisis y los padres reportan mejoras importantes en otros dominios como atención y comunicación, con lo que esperamos que Takeda considere CDD como otra indicación para soticlestato.

• Corregir los problemas en las otras proteínas: si sabemos qué proteína no funciona bien al faltar CDKL5 podríamos ir directamente a arreglarlas y compensar por la falta de CDKL5. En este punto hubo un descubrimiento muy importante este año, al que dedico la sección siguiente entera.

• Aportar más proteína: el desarrollo de terapias de reemplazo enzimático para CDD (cuando produces la proteína en el laboratorio para dársela a los pacientes) ha resultado ser tremendamente difícil. Maria Luisa Tutino presentó en el Foro su trabajo para conseguir la producción de proteína CDKL5 funcional en el laboratorio para usarla como terapia, y los desafíos con los que se iba encontrando y que van solucionando uno tras otro. Yo espero que se unan más investigadores y empresas a intentar conseguir una terapia de reemplazo enzimático para CDD porque hace mucha falta y es muy complejo.

• Arreglar el ARN mensajero: el gen CDKL5 se copia en ARN mensajero, y este a su vez sirve de instrucción para hacer la proteína CDKL5. Hay varias estrategias para intentar sacar proteína funcional a partir de un ARN mutado, y en el Foro vimos una estrategia en Boston para hacer oligonucleótidos antisentido (ASOs) que es un tipo de terapia disponible en otras enfermedades genéticas. Estos ASOs servirían para ciertas mutaciones en CDKL5, no todas, por ejemplo para intentar leer el ARN cuando hay mutaciones de “splicing” o si hay algún cacho de CDKL5 menos importante, haciendo que la célula se salte la lectura de ese trozo del ARN (salto de exón). Hay ejemplos de estas estrategias en la atrofia muscular espinal y en Duchenne, pero para CDKL5 apenas están empezando.  

• Reactivar la segunda copia del gen CDKL5: tuvimos dos presentaciones de grupos que buscan usar una especie de CRISPR para llegar a la copia inactiva de CDKL5 (en niñas) y hacer que se exprese. El invesitgador Kyle Fink lleva años liderando uno de esos proyectos y le acaban de conceder cerca de un millón y medio de dólares para avanzar su terapia génica para CDD (que hace que se lea la segunda copia). Esta año recibió el premio al mejor Laboratorio del Año en el Foro CDKL5.  

• Arreglar el gen mutado: hay varias estrategias en desarrollo para corregir las letras en un gen, o para poner una letra que falta. Majid Jafar, co-fundador de la Fundación Loulou, nos explicaba que a Loulou le falta una letra en el gen CDKL5 y que al saber el diagnóstico su madre se preguntaba “¿y por qué no le ponen la letra que falta y ya está?”. Pues el investigador David Liu está usando también una especie de CRISPR que se llama “prime editing” para hacer justamente eso, poner las letras que faltan. Nos enseñó cómo ya pueden arreglar el gen CDKL5 de niños como Loulou en células en el laboratorio, y actualmente están trabajando en hacer que funcione en ratones. Este tipo de edición genética está empezando ensayos clínicos en otras enfermedades y se descubrió hace apenas 5 años. El objetivo de David no es ya solo poner o quitar una letra, sino como nos dijo “cambiar el gen entero por una copia buena”. Las presentaciones que da este hombre son siempre una ventana hacia el futuro.

• Aportar una copia nueva del gen: esta es la terapia génica clásica, en la que los científicos usan un virus (generalmente uno llamado AAV) para llevar el gen que falta a las neuronas. Ese virus no se multiplica, sino que sirve para llevar el gen a las neuronas y que a partir de ese día ya puedan producir la proteína, en este caso la de CDKL5. En el Foro 2022 tuvimos el notición de Ultragenyx de que su terapia ahora avanza hacia la fase de ensayos clínicos.

4. UN DESCUBRIMIENTO MUY IMPORTANTE PARA ENTENDER CDKL5

Vimos muchas presentaciones en el Foro sobre entender mejor cómo funciona la proteína CDKL5 y las consecuencias de su falta para el cerebro. Pero solo voy a hablar de una en este resumen, porque es un descubrimiento fantástico que ayuda a entender lo que hace la proteína y lo que pasa en la enfermedad. También es una puerta abierta a diseñar nuevos tratamientos.

El descubrimiento nos llega del laboratorio en Londres de Sila Ultanir. La proteína CDKL5 es una kinasa, que son proteínas que lo que hacen es modular la función de muchos otros tipos de proteína. Esto multiplica los problemas, porque cuando falta la enzima tienes también todas esas proteínas que no funcionan bien. El grupo de Sila ha descubierto una proteína muy importante de esas que necesitan a CDKL5 para funcionar bien, y resulta ser un canal de calcio (Cav2.3). Cuando falta CDKL5, ese canal de calcio de abre bien pero luego se cierra muy despacio, lo que lleva a demasiado calcio pasando por el canal.

Estos es muy importante porque muchos de los síndromes de neurodesarrollo con epilepsia están causados por problemas con canales iónicos, las llamamos las canalopatías. Por ejemplo el síndrome de Dravet es por falta de canales de sodio, y la epilepsia por KCNQ2 es por mutaciones que dan demasiada actividad a canales de potasio. Curiosamente hasta hay un síndrome ultra-raro causado por tener el canal de calcio Cav2.3 demasiado abierto, y eso es justamente lo que han visto que pasa también cuando falta CDKL5. Esto era inesperado, pero explica muchas cosas.

Y digo que es un descubrimiento muy importante por dos razones:

1) Muchas veces nos preguntamos… si CDD está causado por faltar una kinasa por qué se parece tanto a algunas canalopatías. Ahora sabemos la respuesta: ¡CDD es parcialmente una canalopatía!

2) Este descubrimiento abre las puertas a diseñar nuevos tratamientos dirigidos a corregir las consecuencias de la falta de CDKL5. Ahora sabemos que queremos que alguna empresa desarrolle un fármaco bloqueante de Cav2.3.

5. MUCHO PROGRESO AMPLIANDO LA CAJA DE HERRAMIENTAS DE INVESTIGACIÓN

Para poder entender qué hace CDKL5 y probar terapias antes de que lleguen a ensayos, los científicos necesitan modelos de la enfermedad en animales o en células en cultivo. Y ha habido un esfuerzo de titanes por parte de investigadores en muchos países para encontrar animales o tipos de cultivo celular al que la ausencia de CDKL5 le provoque síntomas claros (lo que llamamos fenotipos).

Y en investigación casi siempre se usan ratones y ratas modificados genéticamente para tener el mismo problema que la enfermedad en humanos. Pero este año vimos presentaciones de equipos que están ampliando la caja de herramientas de investigación de solo ratones y ratas a incluir muchos otros, como peces, moscas, renacuajos y hasta cerdos con deficiencia en CDKL5.  

Vimos ponencias de dos equipos usando peces cebra como modelo de deficiencia en CDKL5, uno de Portugal y uno de Boston. Los peces tienen algunos de los problemas que vemos en personas afectadas, por ejemplo problemas óseos, y están buscando hacer peces a los que les falte CDKL5 solo en la mitad de las neuronas que es lo que pasa en niñas y por tanto es la mayoría de los casos.

Mis presentaciones favoritas sobre modelos de deficiencia en CDKL5 fueron dos:

• El laboratorio de Ibo Galindo, en Valencia, ha hecho moscas de la fruta (o mosca del vinagre) con deficiencia en CDKL5 y visto que desarrollan epilepsia y su enfermedad es tan severa que hasta viven menos que las moscas sin modificar. Lo curioso es que las moscas solo tienen un gen CDKL, en vez de cinco como las personas, con lo que a estas moscas ¡les falta el equivalente de CDKL1/2/3/4 y 5! Y les produce los mismos síntomas que tienen moscas de otras epilepsias genéticas, las de CDKL5 incluso tienen cambios en su comportamiento. Las moscas de la fruta son de mucha utilidad como herramienta de investigación genética, porque se le pueden quitar y poner genes y ver su función, o en este caso darles los genes humanos de los cinco CDKL y ver cuales les corrigen la enfermedad.

• La empresa Vyant está usando células madre de niños con CDKL5 para producir organoides. Los organoides son como una pelota de neuronas y otras células cerebrales todas producidas a partir de las células madre que se sacan de la piel o muestra de sangre con lo que llevan el ADN de los niños, y que forman en cultivo como un mini-cerebro (en la foto son la bola que está a la derecha del todo). Pues resulta que los organoides de niños con CDKL5 tienen la versión in vitro de epilepsia, que son descargas eléctricas hipersincronizadas. Y lo están usando como plataforma de cribado de fármacos y ya han encontrado algunos compuestos.  

Lo que más me impresiona es la tenacidad de tantos científicos haciendo un esfuerzo de gigantes para no dejar piedra sin remover, mirando en cada animal y cada tipo de cultivo celular y buscando la forma de encontrarle la señal de la falta de CDKL5. Gracias a eso hoy tenemos un abanico de modelos animales y celulares que permiten hacer muchas preguntas científicas, tanto de biología como de tratamientos, y este tipo de trabajo requiere un gran esfuerzo de grupo, no lo puede hacer un laboratorio solo. Y de eso trata la sección siguiente de este resumen.

6. “ESTAMOS EN ESTO JUNTOS”

Hay un mensaje que se convirtió en el lema del Foro 2022, y es “estamos en esto todos juntos”. Lo oímos en palabras pero también lo vimos en acciones. Estos son solo algunos de los ejemplos que vimos durante el Foro:

• Que no se quede nadie atrás. Hay personas con CDD en todos los países, y eso implica también que son personas con todos los idiomas. Por desgracia la barrera lingüística es una de las principales barreras a la hora de llegar a la comunidad internacional de pacientes. Para poder reunir datos de tantos afectados por CDD como sea posible, y poder mantenerles informados de noticias como ensayos clínicos, el registro CDKL5 Registry está disponible desde hace poco en la mayoría de los grandes idiomas: Inglés, Español, Francés, Alemán, Italiano, Árabe, dos versiones de Chino, Japonés y Ruso. Ha sido un trabajazo pero estamos en esto todos juntos.

• Empresas colaborando en estudios clínicos. Cuando nos vimos la última vez en Boston en 2019 lanzamos la propuesta de que hacía falta hacer un estudio clínico en CDD para validar escalas clínicas (para verificar que sabemos medir los síntomas de CDD de la forma que hace falta para ensayos clínicos). Y lo que pedíamos no era simple, porque nuestra propuesta es que fuera solo un estudio en el que colaboraran todas las empresas, co-diseñándolo y ejecutándolo juntas, para así no duplicar (o quintuplicar) esfuerzos y sobrecargar a las familias. Este año Xavier Liogier, de la Fundación Loulou, nos hablaba desde ese mismo escenario pero esta vez para anunciar que ya ha entrado el primer paciente a ese estudio clínico, llamado CANDID, que incluye muchos países incluida España. Entre esas dos ponencias ha habido muchísimo trabajo, incluso llevamos el estudio a examen por la agencia americana del medicamento, y también ha supuesto un importante paso hacia la colaboración por parte de las 7 empresas que se juntaron para hacer el estudio posible. Estamos en esto todos juntos.

• Colaboraciones preclínicas. La comunidad de investigadores en CDKL5 siempre ha sido excepcionalmente colaborativa, y el Foro tiene una serie de sesiones de grupo en la que nos coordinamos. Este año salió la propuesta de que las empresas que están buscando terapias para CDKL5 se unan a esas colaboraciones preclínicas (de investigación en animales) porque suelen estar presentes en la conversación pero lo que no hacen es abrir sus libros de laboratorio y enseñarnos los datos. Lo que se busca es que los investigadores trabajando con ratones con CDD en universidades y en empresas se puedan sentar juntos y comparar resultados y poder así validar los mejores síntomas en ratones que podemos usar para investigar (los síntomas más robustos y mas reproducibles entre laboratorios). Los grupos académicos ya lo hacen y el objetivo es que se unan los de las empresas. Espero que el año que viene en el Foro 2023 podamos confirmar que hemos abierto la colaboración y que se han unido a un esfuerzo tan necesario, porque estamos en esto todos juntos.

• La Alianza internacional ayuda a acelerar estudios clínicos. Una dificultad habitual de los ensayos clínicos en enfermedades raras es que les cuesta mucho a las empresas identificar los hospitales que hacen falta. La Alianza Internacional de CDKL5 ha compilado una lista de los hospitales de cada país de la alianza en los que los miembros tienen médicos de confianza con experiencia en CDD. En el Foro aprendimos que esta lista ha facilitado y acelerado la identificación de hospitales para el estudio CANDID, y espero que también acelere los futuros ensayos clínicos. Estamos en esto todos juntos.

• El liderazgo de las familias CDKL5. El Foro CDKL5 es una conferencia médica y científica, donde nos reunimos para repasar los últimos avances y para organizarnos de cara a seguir avanzando. Pero también se trata de un congreso liderado por los padres de una niña con CDD, donde las familias tienen un papel prominente tanto en la agenda como en las conversaciones. Abrimos el Foro con las palabras de Natalie Ladly, de CDKL5 Canada, que compartió con todos nosotros lo que supone para su familia vivir con CDD (#brynnstrong!). Luego durante la cena de gala Simon y Fiona Walsh de CDKL5 Irlanda también nos abrieron las puertas de su casa y su familia, y para cerrar el congreso Rick Upp, de la IFCR, nos hizo un resumen de lo que ha pasado este último año en la comunidad de pacientes. El premio al “Paladín del Progreso” que da el Foro cada año a las personas que más impacto han tenido en CDKL5, fue este año a Antonino Caridi, de CDKL5 Italia, uno de los líderes mas querido y respetado de la comunidad de pacientes en su lucha por una cura para CDD. Y tuvimos representantes de pacientes de 14 países (¡ya hay más de 30 en la Alianza!) que participaron en el Foro, mezclándose con investigadores y participando de manera activa en las conversaciones, sobretodo durante las sesiones de debate. Es así que a través de sus palabras y sus acciones las familias CDKL5 nos enseñaron durante el foro que estamos en esto todos juntos.

RESUMEN

Si se puede resumir el Foro de 2022 en unas pocas frases, sería:

No hay enfermedades intratables.

CDD es ahora parte del 5% de enfermedades raras con un tratamiento aprobado.

La terapia génica viene a ensayos clínicos.

Y desarrollo de una terapia a través de ensayos clínicos siempre es difícil pero estamos en esto todos juntos.

La Fundación Loulou fue fundada en 2015 con la misión de tener “tratamientos para CDD en ensayos en 2020, y curas en ensayos en 2025”. En aquellas fechas no había ni un solo fármaco en desarrollo para CDD, pero si que había fe en la ciencia y en el poder de crear una comunidad en torno a una enfermedad rara. Tras las noticias del Foro 2022 ahora ya sabemos que es realista pensar que incluso antes de 2025 habrá personas que hoy viven con CDD que habrán recibido una terapia génica como parte de esos ensayos clínicos. Este ha sido sin duda muy buen año para la investigación en CDKL5.

Espero que os haya gustado el resumen. Ya me diréis lo que os parece en los comentarios.

Ana Mingorance, PhD

Nota: este texto captura mis impresiones de las presentaciones del Foro que más me interesaron como científico y como defensora de los pacientes, 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.