How close are we to creating transgenic people?

crispr dravet

The journal Nature just released one of the most anticipated breaking news of the last few years: CRISPR gene editing has been tested in a person for the first time.

In my day-to-day work I interact with families that have a child with a genetic disease. These are diseases where the mutation is produced “de novo”, which means that it happened during the production of the baby. The family didn’t carry any mutation and most likely that child is the only one with that exact mutation, or one of a handful world-wide. 

As you can imagine, ever since scientists announced they had found a way to do copy-and-paste in DNA to introduce or to correct mutations I get one question a lot: how close are we to turn that discovery into a therapy for people with genetic diseases?

And despite the breaking news from Nature the answer is still “not that close”.

Let me elaborate on that.

Before being available as a treatment for people born with genetic mutations the CRISPR technology needs to go through roughly four steps:

  1. Show that CRISPR can correct mutations in human cells in a test tube. This was the groundbreaking discovery that got us started in an amazing medical development explosion.
  2. Show that these genetically-modified cells can be delivered to patients. This is more cell therapy than gene therapy and it is very useful on its own. Likely to be the first path forward for the CRISPR approach.
  3. Show that we can actually correct mutation in patients using CRISP. Now we are talking about gene therapy, and for years this will have to be done in clinical trials under controlled conditions.
  4. Finally, get approval for gene therapy using CRISPR technology so that we can fix patient’s mutations, effectively creating transgenic people.

What Nature announces is that scientists at Sichuan University have treated a patient with lung cancer with cells that had been reprogrammed using CRISPR before being delivered into the patient. This is step 2.

It had also been done before using other technologies that enable gene-editing, also in diseases where scientists first modify those cells outside the body and then deliver them to the patient, such as in cases of leukaemia or HIV. CRISPR is predicted to be the most powerful (and easy!) of these methods and is likely to be the one that will become a real treatment so reaching step 2 is great news.

At this second stage, these are all “ex vivo” approaches where the gene editing technology is applied to the cells that will be used to treat the patient, instead of using the technology directly in the patient.

The move towards step 3, editing the patient DNA, opens serious safety concerns:could the gene-editing enzymes cut and paste more letters in the DNA that they were intended to? Could they cause unwanted mutations? Because of that, it is likely to happen first in very localized indications such as tumours or retinal disease.

Moving from those localized diseases to more widespread ones will have the same challenges to reach the target organs that “traditional gene therapy” currently has. For the non-initiated, “traditional gene therapy” doesn’t change the patient DNA, instead it uses virus that have been stripped of the virus DNA to infect the patient and deliver a healthy version of the gene that the patients have mutated. At the end the patient has his own genes plus this new therapeutic gene. And that is not easy to do in hard-to-reach organs such as the brain!

Because delivering the CRISPR enzymes will also rely on viral vectors, even if CRISPR was proven today to be totally safe we wouldn’t know how to apply it to the brain tomorrow, since we still haven’t mastered that delivery aspect yet.

For any patient with a neurological condition caused by de novo mutations (so mutations unique to him/her) this is how the things to do list looks like before we can treat him:

  1. CRISPR needs to be proven safe in small regions (step 3)
  2. We need to find good viral vectors to deliver genes to the brain, which is larger than the eye or blood cells and happens to come inside of a hard box.
  3. Those viral vectors also need to be safe.
  4. CRISPR will be first used for genetic neurological diseases that are inherited, which means where the same mutation is found in many people.
  5. And only after all that has happened we can think of using CRISPR therapy when the target mutation is unique for each patient, which introduces additional questions: can we get approval for the disease and just change the target sequence that the CRISPR uses? Will companies ever manufacture separate ones for individual patients?  etc

So for the patients I work with, who carry de novo mutations that cause neurological diseases, the answer to how close we are to use CRISPR as a therapy for people like them can only be “not that close”. These are probably the last diseases to benefit from the gene editing technology.

In the mean time we celebrate that we have reached step 2 with CRISPR, delivering edited cells to a patient, and keep our eyes on that next frontier: the in vivo experiment, the first patient that has his own DNA corrected using CRISPR in a clinical trial, the first transgenic people.

Let me know what you think about it in the comments.

Ana Mingorance PhD

Originally published in LinkedIn on November 16, 2016