The “Cell and Molecular Orchestration in Muscle Regeneration, Ageing and Diseases” team, at the Institute’s Myology Centre for Research, which is co-directed by Capucine Trollet and Vincent Mouly, has just published an article relating to the transduction efficiency of different AAV serotypes after a local intramuscular injection. Interview with Capucine Trollet, who directed this work.
Why did you focus on showing the differences in efficiency between different AAV serotypes?
Our goal was to compare AAV serotypes after a local intramuscular injection (as opposed to a systemic injection) in mice and in humans. It is widely described in the literature that the AAV8s and AAV9s are very effective in muscle, but by a systemic injection and in mice. We wanted to see what the situation would be after a direct injection and in humans.
We have been working for 2 years on putting in place a xenograft model for human muscle in immunodeficient mice (thanks to financing from the Fondation de l’avenir (Foundation for the future), the Fondation pour la Recherche Médicale (Foundation for Medical Research), and to a close collaboration with MyoBank). This model – initially described by and Katherine Wagner – allows us to keep a fragment of human muscle “in vivo” to study its regeneration and to test therapies. One of the big innovations in this article is that we combined the xenograft model with an AAV injection. Thus, we were able to test the AAV8 and AAV9 serotypes “in vivo” in a human context.
What conclusions do you draw from this work?
In our article, we show that in xenografting, the AAV8s and AAV9s have a similar efficacy and muscle fibrosis does not prevent the transduction of the muscle fibres.
For several years now, we have been developing a viral gene therapy approach for OPMD by the extinction/replacement of PABPN1. The goal of this strategy would be a local injection of the AAV9 vectors into the muscles of the pharynx. We know that these muscles are highly fibrotic. Our results are therefore reassuring from this point of view.
How can these results be useful in influencing therapy protocols for neuromuscular or other types of disease?
Although they don’t really influence future protocols, these results confirm the results obtained by systemic injection regarding the efficacy of these serotypes and they describe for the first time the behaviour of these vectors in a “human” muscle.
What are the next stages?
The xenograft model allows us to test therapeutic strategies in a human context. The next stages will be to test other vectors and other therapeutic strategies with a particular interest in the targeting of muscle fibrosis and improvement in muscle regeneration.
