Efficacy, pharmacokinetics, and safety in the mouse and primate retina of dual AAV vectors for Usher syndrome type 1B

• DOI: 10.1016/j.omtm.2023.02.002
• Publication Date: 2023-02-11T02:35:55Z
• Authors: Rita Ferla; Fabio Dell’Aquila; Monica Doria; Maria Ferraiuolo; Alessia Noto; Fabiana Grazioli; Virginia Ammendola; Francesco Testa; Paolo Melillo; Carolina Iodice; Giulia Risca; Novella Tedesco; Pierre Romain le ...; Enrico Maria Surace; Francesca Simonelli; Stefania Galimberti; Maria Grazia Vals...; Jean-Brice Marteau; Philippe Veron; Stefano Colloca; Alberto Auricchio
• Keywords: Usher syndrome

Gene therapy of Usher syndrome type 1B (USH1B) due to mutations in the large Myosin VIIA (MYO7A) gene is limited by packaging capacity adeno-associated viral (AAV) vectors. To overcome this, we have previously developed dual AAV8 vectors which encode human MYO7A (dual AAV8.MYO7A). Here show that subretinal administration 1.37E+9 1.37E+10 genome copies a good-manufacturing-practice-like lot AAV8.MYO7A improves retinal defects mouse model USH1B. The same was used non-human primates at doses 1.6× and 4.3× highest dose proposed for clinical trial based on efficacy data. Long-lasting alterations function morphology were observed following high dose. These findings modest improved over time low-dose group, as also other studies involving use humans. Biodistribution shedding confirmed presence vector DNA mainly visual pathway. Accordingly, detected mRNA expression predominantly retina. Overall, these pave way translation AAV USH1B subjects.