Gene therapy for inherited retinal degenerations.
Gene therapy is quickly becoming a reality applicable in the clinic for inherited retinal diseases. Progress over the past decade has moved proof-of-concept gene therapies from bench to bedside. The remarkable success in safety and efficacy, in the phase I/II clinical trials for the form of the severe childhood-onset blindness, Leber's Congenital Amaurosis (LCA) type II (due to mutations in the RPE65 gene) generated significant interest and opened up possibilities for a new era of retinal gene therapies. Success in these clinical trials was due to combining the favorable features of both the retina as a target organ and adeno-associated virus (AAV) as a vector. The retina offers several advantages for gene therapy approaches. It is an anatomically defined structure that is readily accessible for therapy and has some degree of immune privilege, making it suitable for application of viral vectors. AAV, on the other hand, is a non-pathogenic helper dependent virus that has little immunogenicity. This viral vector transduces quiescent cells efficiently and thanks to its small size diffuses well in the interneural matrix, making it suitable for applications in neural tissue. Building on this initial clinical success with LCA II, we have now many opportunities to extend this proof-of-concept to other retinal diseases. This article will discuss what are some of the most imminent targets for such therapies and what are the challenges that we face in moving these therapies to the clinic.
INSERM, U968, Institut de la Vision, 17, rue Moreau, 75012 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (Paris-6), UMR S968, Institut de la Vision, 17, rue Moreau, 75012 Paris, France; CNRS, UMR 7210, Institut de la Vision, 17, rue Moreau, 75012 Paris, France. Electronic address: deniz.dalkara@inserm.fr.
Deniz
D
Dalkara
INSERM, U968, Institut de la Vision, 17, rue Moreau, 75012 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (Paris-6), UMR S968, Institut de la Vision, 17, rue Moreau, 75012 Paris, France; CNRS, UMR 7210, Institut de la Vision, 17, rue Moreau, 75012 Paris, France; Fondation ophtalmologique Adolphe-de-Rothschild, 75019 Paris, France; Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, 75012 Paris, France; Institute of Ophthalmology, University College of London, London EC1V 9EL, United Kingdom; Académie des sciences, Institut de France, 23, quai de Conti, 75006 Paris, France.
José-Alain
JA
Sahel
D001766:Blindness / Q000628:therapy; D002986:Clinical Trials as Topic; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D034622:RNA Interference; D012162:Retinal Degeneration / Q000235:genetics / Q000628:therapy*
AAV; Dégénérescences rétiniennes héréditaires; Facteurs trophiques; Gene therapy; Inherited retinal degenerations; Optogenetics; Optogénétique; RdCVF; Thérapie génique; Trophic factors