Genethon, a laboratory created by the patient organization AFM-Telethon, is one of the world’s leaders in the development of biotherapies for rare diseases. In this interview Genethon’s CEO Frédéric Revah explains its role in the discovery of innovative therapies since the 1990s and the recent launch of YposKesi, its innovative (and profitable) manufacturing platform.   Could you introduce Genethon to our international audience? The creation dates back to 1990, when AFM-Telethon decided to create an institute for the development of therapies for rare genetic diseases. Today, in a time when the field of gene therapy is experiencing an exponential growth, Genethon is probably a pioneer, as it is one of the oldest organization completely focused on this field in the world. We started in 1996-1997, when the industrial interest in gene therapy was decreasing. Indeed, at the beginning of the 1990s, there had been some interest in gene therapy, as it was seen as a possible way to treat any disorder, including frequent and non-genetic ones. Soon, it became clear that the field would not deliver such results, and the industrial players withdrew. However, the Association Française contre les Myopathies AFM-Telethon (the French Muscular Dystrophy Association) firmly believed that gene therapy could be a game changer in rare genetic disease, and, through Genethon, it heavily invested in the field. To put this into context, in that period, France was leading the research in gene therapy. In 1999, Prof. Alain Fischer performed the first successful trial at the Hôpital Necker, demonstrating the possibility to treat immune-deficient babies by gene therapy, transferring corrective genes in their immune system cells. In this way, the immune functions were restored, and the treated children, who had originally an expected life-span of 3-4 years constrained in a completely sterile bubble, were able to live and grow.   What has been the evolution of Genethon since its creation, and how would you describe your main achievements? In the 1990s, the human genome had not been deciphered yet. The first step after the foundation of the organization was to participate in the global effort. The first high resolution map of a genome was finally reproduced at Genethon between 1992 and 1996, by the team led by Jean Weissenbach and Daniel Cohen. Though it was just the first step, it was a critical move for a faster identification process of the genes responsible for genetic diseases. Following this incredible and early success, Genethon focused on therapy. Indeed, our objective was not to be a genetic institute, but rather to develop the tools and the know-how for the design, testing and manufacturing of gene therapy programs. After 10 years of learning, we started manufacturing in 2006. Biomanufacturing was a critical step to develop clinical trials. We upgraded our small twenty-person facility to one of 5000 sqm in 2013, and it was at that time the largest gene therapy manufacturing facility in the world. After this milestone, Genethon started developing products for rare diseases in different therapeutic areas, such as immune, blood, neuromuscular, liver and retinal disorders. Right now, we have eight products in clinical trials: some of them have been completely developed in-house, others through external collaborations. Let me give some examples of our successes. Genethon discovered and patented a gene-therapy product for spinal-muscular atrophy the product was licensed and developed by AveXis, now owned by Norvartis, and they are still operating under a license from Genethon. Similarly, the leading product of Audentes Therapeutics, a West Coast company listed on the NASDAQ, was developed here up to the animal testing phase. Clinical trials started one year ago and we are witnessing spectacular results. We have outlicensed a product to Orchard Therapeutics, and we are co-developing a Duchenne dystrophy program with Sarepta, a US biopharma listed on the NASDAQ. The list of licensed products is long. Similarly, in other cases, we have continued development in-house through international trials.   Genethon has quite a unique model. What is the effect of such a model on your research? Our founder is a patient organization, making us a unique case. You could see us as the laboratory of a patient organization, as a biotech company, a portfolio of licensed or internally-developed compounds, and a nonprofit, all at once! Contrary to the common perceptions of nonprofits, there is a economical value to our activities: today around 60% of our funding comes from AFM-Telethon but we are steadily increasing the portion that is derived from licensing revenues. Nevertheless, we would never have achieved what we did in the field of genetics if we were a regular for-profit company. Back in the 1990s, no investor would have invested for that long in a field considered as dead, and up to 2011, no pharmaceutical company would have put a dime into gene therapy. So, it is safe to say that the nonprofit status is a fundamental aspect.   You have been at the helm of the organization for eight years. What would you like Genethon to become in the next eight years? I want Genethon to be the leader in two aspects. The first is the design and technical evaluation of gene therapy, in particular for neuromuscular diseases. To achieve this objective, it is important to adopt a multifaceted approach by working with the best muscle physiologists, the best clinicians, and the best scientists. We need to reach new heights in clinical evaluation, pre-clinical science and physiology. We need to understand the expectations of the patients, the molecular and cellular mechanisms that we want to target with our products and the appropriate predictive models for degenerative diseases. The second point, and this is what makes gene therapy unique, is manufacturing. Its cost is spectacular, in particular for neuromuscular diseases. Today, the production of a single dose for the treatment of a Duchenne muscular dystrophy needs a 200-liter bioreactor, which would be enough to produce thousands of doses of other type of products such as vaccines. The methods, the technologies, and the processes need to be significantly improved. On one side, there is the opportunity for incremental advancement, aimed at gaining a few percentage points. On the other, there is space for game-changing improvements that would reduce costs by a factor 20, or even a 50. Gene therapy has a unique feature: a very large part of the final value derives from manufacturing. This aspect is so vital that at Genethon we have a whole team dedicated to innovations for manufacturing. In particular, having YposKesi [an expert industrial platform exclusively dedicated to gmp manufacturing and development of gene and cell therapy products. The company was founded by AFM-Telethon in 2016 together with BPI-France to cover the needs of Genethon lab and serve as a CDMO for third parties. It is across the street and this is very important in this aspect.   In the same way France has been a pioneer in gene therapy, do you think that it has the potential to become one of the first nations to innovate the manufacturing process? This is at stake. If we are not able to innovate in manufacturing, the products invented in France will have to be produced elsewhere. It would be an incredible loss in economic value for our country. Of course, we are not trying to do this all by ourselves; we are trying to get the support of the authorities and the involvement of industrial players.   What do you think are the strengths of France in gene therapy?

The strength lies in the fact that there is a strong expertise on the scientific and the clinical side of things. What we are missing and what we are trying to bring to the table with YposKesi is the industrial element attached to it