A noticeable trend at last week’s American Society for Gene & Cell Therapy (ASGCT) conference was one of retrospection in the face of progress. In many cases, speakers expressed the need to reflect on the history of their field and the progress made over the past few decades to aid in decision-making for future endeavors.

Frederic RevahFrédéric Revah, PhD, is one such scientist who has consistently considered the history of biotechnology, research, and pharmacology. As the CEO of Généthon, Revah has reflected on the history of the non-for-profit’s origins to direct the next steps for the organization, and those organizations that have branched out of it.

Revah sat down with GEN’s managing editor, Corinna Singleman, PhD, to discuss the past, present, and future of Généthon and particularly its pioneering research in muscular dystrophy.

Généthon was created and funded by the French Muscular Dystrophy Association, AFM-Telethon in 1990. AFM-Telethon arose from the grass-roots efforts of nine families advocating for study into Duchenne muscular dystrophy (DMD) and hosting telethon events beginning in the 1950s. They began a national phenomenon in France to raise awareness and funding for muscular dystrophy research, which has expanded to study other rare genetic disorders.

Généthon was created with a primary focus on research in gene therapy. Initially, this work concentrated on better understanding the human genome as a whole, as researchers around the world were working on the Human Genome Project. With the successful sequencing of the human genome, Généthon’s goals refocused on gene therapies, culminating in its first gene therapy trial for severe combined immune deficiencies (SCID).

“Généthon progressively constructed the competencies, the know-how in designing those drugs, testing them, manufacturing them. We were involved in manufacturing as early as 2008… The idea is that, if we didn’t have manufacturing tools, we would go nowhere.”

Through strategic partnerships and collaborations, Généthon has continued to grow in its research abilities as it develops therapies, bringing many treatments to clinical trials.

This interview has been edited for length and clarity.

Singleman: How would you describe your contribution since you joined Généthon as CEO? Have you changed or modified the direction of where the company was going to where it is now?

Revah: I came in 2010 at a moment when there was no clinical trial ongoing, with the mandate to transform what was a very efficient research institute into some kind of not-for-profit biotech. And now, 14 years later, we have this pipeline and industrial partnerships. I had an initial academic background then moved to the pharma industry. And it’s really with that training, bringing my pharma expertise to the association, ready to have this shift from an R&D institute to a more biotech type of operation. That’s where we are today, trying to secure industrial financing and move progressively from discovering drugs, to using those drugs in the clinic, and possibly moving to the next step of taking some of those drugs to the market ourselves. This is a challenge and an endeavor because the number of resources that is needed is very high to achieve this transition in an environment that is not very easy for rare genetic diseases.

Gene therapy for rare diseases was not of interest for investors or for pharma. Things changed with the first initial “Wow!” results that were so impressive. Then pharma got interested and then realized that for rare genetic diseases, by definition, the market for the business model based on recouping the investment on one single injection for a small population was a challenge.

It does worry me. We’re seeing in the pharma industry, some of the players stepping back from their investment in rare disease. See what happened with Pfizer. And we see pharma company, biotech investors in particular, in this moment where access to capital is difficult, are still interested in gene therapy but for larger markets. Our challenge in the coming years will be to try to find the right balance to move those drugs forward, but under strained financial conditions.

Singleman: In some of the talks at ASGCT, there has been discussion about rare diseases through the lens of how to apply those therapies to more common diseases, like heart disease which is one of the top killers. What are your thoughts on that?

Revah: You should not neglect the fact that rare diseases are a public health issue. There are thousands of these diseases. Three hundred million people around the world are affected by them and there’s many of those individually that could benefit from gene therapy. Whatever we do for rare diseases also benefits frequent disorders and working on rare diseases allows us to develop technologies, develop approaches, develop science, and it’s really a springboard for more common diseases.

There are only a few kids per year in Europe, probably a similar number of kids in the United States, with DMD. The work to study and treat this disease is now applied to cancer with CAR T cells because CAR T cells are really the extension of the same type of technology, and now we can think about heart disease and diabetes. The research into rare diseases really feeds research for widespread diseases and rare disease research should not neglected.

There is a systemic question then about how do we finance development for these rare genetic diseases? The Bespoke Gene Therapy Consortium (BGTC) is an organization launched by the FDA and National Institutes of Health (NIH), trying to finance developments for some genetic diseases with no commercial models. Their symposium exemplified how the fight of parents has been important. But this is not sufficient. We have to find a systemic way in addressing the financing and it’s not only regulatory. Peter Marks (FDA) said that we have to be pragmatic and we have to adjust the regulatory hurdles throughout the season. That’s good but it doesn’t solve the cash problem.

Généthon is one of the pioneers in gene therapy. We’re probably one of the oldest organizations in the room working on gene therapy. It started in the ‘90s at a time when nobody was, and we were still one of the leaders in the sense of the breadth of our portfolio. We work not only on therapies, but on some technologies. We are convinced that bringing down the cost of production is key.

Singleman: How are you doing that?

Revah: We have a group of 40 people working on that, in close conjunction with the production side. We were pioneers, for instance, in suspension methods; we have been using cell suspension methods at a time when everybody was using a different method. The scaling up becomes much easier when the cells are in suspension. We’re trying to find new production systems, new production cells. We are also trying to improve the transfection step, which is very important. We’re trying to improve downstream methods and purification methods.

I would say incremental improvement of the process, but also trying to bring some breakthrough approaches in the way plasmids are designed and moving to plants for instance, which is something that we’re testing. It could be a breakthrough approach and the objective here is really to decrease the cost of production. Some of these productions could be as expensive, from a few hundred thousand [Euros] per dose. I’m just talking about cost of production, cost of goods, bringing that cost down is also an important element in making development affordable.

Singleman: If we’re going to have these treatments, there needs to be some equity in distribution. Is all this manufacturing bioprocessing work being done in-house or do you also work with corporate partners?

Revah: We strongly believe that improving bioprocessing is really a transdisciplinary approach because you have to understand how these viruses assemble in cells. We ask questions: What’s the transfection? How are these bioreactors working? It’s really a mix of virology, cell biology, instrumentation sensors, and more, because in order to understand what happens in vivo, you have to develop sensors and we use artificial intelligence to assess the data that comes out and try to improve. So basically, we’re not doing all that by ourselves, trying to create networks. We’re working with AI specialists, in virology and cell biology. We’re working with solution providers, getting people in other fields interested in the gene therapy arena. We believe that there’s technology out there that we should at least test. So yes, we’re not doing it on our own.

Singleman: Is there anything exciting or interesting coming up with either partnerships or any new trajectories in your research or processing that you are looking forward to?

Revah: We’re working on producing AAV in plants, also very systematic genetic engineering of production cells in order to be able to identify those genes that might modify and improve productivity. That’s something that we’re doing in a very systematic way. We’ve been working on AI with a very large conglomerate and the defense industry in France. The idea is really to create a numerical twin of our bioreactors. For the time being, we’re trying to segment the process and we have been concentrating on the downstream process. We’d like to be able to predict from the chromatography profile of our products, some very key parameters that we would not have to test in the analytical lab. We’re progressing on that in order to reduce the time and the cost of production.

Singleman: You said you have a lot of stepwise processes that you’re being very precise about. Have there been any pitfalls or areas that are very clearly not working and that need improvement?

Revah: I think the whole industry is facing the same questions. There is a ratio of full to empty to consider. This includes a capsid with the exact genome that we want to put it in, there are the capsids that are exactly the way we want them. But there are capsids that are empty, or capsids that are partially full. This has been a challenge for the whole industry trying to improve this ratio. After all, we’re forcing cells to assemble a virus with DNA, which is not the DNA that is supposed to be there. So how does this happen? And it takes us into both basic virology, and also design of the bioreactors. Without going into detail, we think we have interesting solutions there.

Singleman: You mentioned Pfizer earlier. Do you have any thoughts or comments about the situation with Pfizer’s DAYLIGHT project and the death of the young patient in the project? Généthon has its own clinical trial coming up. Will this sad news impact the trial?

Revah: Of course, we’re following this very closely. We shared information on some of our respective side effects with Sarepta, Pfizer, and Solid Biosciences. We presented what we encountered and the solution we came up with, which was different from the side effect that we’ve seen this week, which is cardiac.

It is another type of side effect that appears almost a year after treatment and so of course, there are some elements that we’re thinking about, having studied the disease for more than 20 years. We will definitely take that into account in our thinking and the way we treat patients.

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