Noninvasive gene delivery to foveal cones for vision restoration

• DOI: 10.1172/jci.insight.96029
• Publication Date: 2018-01-24T16:00:56Z
• Authors: Hanen Khabou; Marcela Garita-He...; Antoine Chaffiol; Sacha Reichman; Céline Jaillard; Elena Brazhnikova; Stéphane Bertin; Valérie Forster; Mélissa Desrosiers; Céline Winckler; Olivier Goureau; Serge Picaud; Jens Duebel; José-Alain Sahel; Deniz Dalkara
• Keywords: Transduction (biophysics); Adeno-associated virus

Intraocular injection of adeno-associated viral (AAV) vectors has been an evident route for delivering gene drugs into the retina. However, gaps in our understanding AAV transduction patterns within anatomically unique environments subretinal and intravitreal space primate eye impeded establishment noninvasive efficient delivery to foveal cones clinic. Here, we establish new vector-promoter combinations overcome limitations associated with AAV-mediated cone fovea supporting studies mouse models, human induced pluripotent stem cell–derived organoids, postmortem retinal explants, living macaques. We show that AAV9 variant provides when injected several millimeters away from fovea, without detaching this delicate region. An engineered AAV2 a well-tolerated dose administered intravitreally. Both modalities rely on cone-specific promoter result high-level transgene expression compatible optogenetic vision restoration. The model systems described here provide insight behavior across species obtain safety efficacy needed therapy neurodegenerative disorders.