INSERM (Institut National de la Santé et de la Recherche Médicale);SORBONNE UNIVERSITE;Centre National de la Recherche Scientifique - CNRS
发明人:
申请号：
EP18701288.5
公开号：
EP3570895A1
申请日:
2018.01.16
申请国别(地区):
EP
年份:
2019
代理人:
摘要：
Intraocular injection of adeno-associated viral (AAV) vectors has been an evident route for delivering gene drugs into the retina. Currently, the vectors need to be injected into the subretinal space in order to provide gene delivery to cones. In this approach, gene delivery is limited to cells that contact the local "bleb" of injected fluid. Furthermore, retinal detachment that occurs during subretinal injections is a concern in eyes with retinal degeneration. Here, the inventors establish several new vector-promoter combinations to overcome the limitations associated with AAV-mediated cone transduction in the fovea with supporting studies in mouse models, human induced pluripotent stem cell-derived organoids, post-mortem human retinal explants and living macaques. They show that an engineered AAV2 variant provides gene delivery to foveal cones with a well-tolerated dose administered intravitreally. The delivery modality relies on a cone-specific promoter and result in high-level transgene expression compatible with optogenetic vision restoration. Accordingly, the present invention relates to method of expressing a polynucleotide of interest in the cone photoreceptors of a subject comprising intravitreal delivery of a therapeutically effective amount of a recombinant AAV2-derived vector comprising a VP1 capsid protein as set forth in SEQ ID NO: 1 and the polynucleotide of interest under the control of the PR1.7 promoter as set forth in SEQ ID NO:2.L'injection intraoculaire de vecteurs viraux adéno-associés (AAV) a été une voie évidente pour l'administration de médicaments de génie génétique dans la rétine. Actuellement, les vecteurs doivent être injectés dans l'espace sous-rétinien afin de fournir une administration de gènes à des cônes. Dans cette approche, l'administration de gènes est limitée à des cellules qui entrent en contact avec la bulle de filtration locale du fluide injecté. En outre, le décollement de la rétine qui se produit pendant les injections sous
