After several years of research to improve the efficacy of viral vectors and therapeutic cells, AGT is today at the heart of translational research in biotherapy for the treatment of rare genetic diseases. These therapeutic projects can develop effectively thanks to the presence on one site of research teams that are closely associated with different technological platforms.
Scientific programs and therapeutic projects.
Over the last 15 years, the different actors of AGT have acquired an expertise in translational research that is unique in France. We focus essentially on translational programs in the fields of neuromuscular disorders (skeletal muscles in particular), the central nervous system and the retina, using vectors derived from AAV, primary cells and also from genetically modified primary cells.
The authorization given by the French Agency for the Safety of Health Products (Afssaps) to conduct gene therapy trials for a retina pathology, Leber’s congenital amaurosis, exemplifies the potential for mobilization and the complementarity of the value chain offered by AGT. The group was able to deliver a solid proof of concept based on extensive evaluation in large animal models present on site which had benefited from anatomopathological analysis, also carried out on site. AGT then developed in-house a complete process of production and purification of the therapy vector, thus responding to the requirements of the regulations in force and developed quality control tests adapted to the characteristics of the product. The group also undertook to transfer the whole of the production and purification process and quality control tests to the Atlantic Bio GMP (ABG) clinical production platform, located in Saint-Herblain, where the production of the clinical batch of the vector was carried out. Finally, with the assistance of the Department of Ophthalmology of the university hospital (CHU), AGT provided the description of the phase l/ll clinical trial. Today, we are still working in close collaboration with ABG for the development of processes adapted to AGT’s various therapeutic projects.
AGT’s scientific programs :
- The improvement of procedures of extraction, selection and amplification of muscle stem cells for the treatment of muscular genetic diseases,
- The constant improvement of the processes of production and purification of AAV-derived vectors, as well as the development of regulatory quality control tests adapted to the therapeutic product. This program is carried out in close collaboration with Généthon,
- The optimization of the routes of administration and the evaluation of the in vivo behavior of therapeutic agents (cell and/or vector),
- The understanding of the molecular mechanisms that support the in situ persistence of the AAV genome,
- The control of the immune response of the host with respect to the therapeutic agent (cell, vector and/or transgene).
These five programs, qualified as “generic”, are at the service of therapeutic projects that are not only internal but also external, notably in collaboration with the Institute of Myology at La Pitié Salpêtrière and the Généthon in Evry.
AGT’s therapeutic projects :
- Cell therapy for Duchenne muscular dystrophy: this group has isolated skeletal muscle cells with the characteristics of muscle stem cells which, once extracted, can be amplified and injected systemically into GRMD dogs, bringing an impressive and persistent therapeutic effect with no secondary effect observed to date (≥ 3 years).
- Gene Therapy of Duchenne muscular dystrophy : AGT is deeply involved in an ‘AFM’ network for the establishment of a clinical gene therapy trial in 2014 for non-ambulatory patients with Duchenne muscular dystrophy. AGT is in charge of the in vivo aspect for the administration of the AAV vector and euthanasia, the biodistribution study, the analysis of the expression of the dystrophin gene, and finally, of the in situ and remote anatomopathological analysis of transduced muscles.
- Gene therapy of the central nervous system: the purpose of this axis is the development of a strategy for intrathecal gene transfer to target the central nervous system (CNS) using AAV vectors. The results obtained aim to set up clinical trials for the gene therapy of motor neuron diseases, as well as other neurodegenerative diseases, such as Friedreich’s ataxia and Pompe disease. They will also contribute to nourish reflection within the Biotherapies Institute for Rare Diseases on strategies regarding SMA.
- Gene therapy of Leber’s congenital amaurosis secondary to mutations in RPGRIP1, PDE6β and RDH12 genes : after several years of effort to obtain a stable colony of dogs bearing a spontaneous mutation in the RPGRIP1 and PDE6β genes, the proof of the concept has just been obtained in these models, establishing that an AAV5 and AAV8 can cause spectacular phenotypic correction enabling the stable correction of vision. These are two examples of the restoration of photoreceptors (cones and rods, respectively).
The AGT conducts its scientific programs and therapeutic projects in collaboration with :
Richard Snyder of the University of Florida, USA (in situ molecular status of the AAV genome); Christian Hamel from the University of Montpellier (therapeutic projects for retinal dystrophies); Thomas Voit from the Institute of Myology at La Pitié Salpétrière ; and Fulvio Mavilio at GENETHON (production and purification processes as well as QC tests of AAV vectors; pharmacodynamic/pharmacokinetic programs of the AAV and the transgene; optimization of the routes of administration of cells and vectors; therapeutic projects for Duchenne muscular dystrophy)
Yan Pereon of the functional exploration service of the University Hospital (CHU) of Nantes, responsible for the Reference Center for Neuromuscular Diseases of Nantes/Angers (cell therapy project for Duchenne muscular dystrophy)
Patrick Aubourg of CHU Bicètre (routes of administration in the central nervous system)
Ignacio Anegon of the University of Nantes (immunology of AAV-mediated gene transfer in macaque monkeys)