Gene therapies for age-related macular degeneration and uveitis (360G-Wellcome-216593_Z_19_Z)

Adeno-associated viral (AAV) vector-mediated retinal gene therapies have demonstrated efficacy and safety in the treatment of inherited retinal dystrophies. We aim to combine established AAV gene delivery platform with CRISPR/Cas9 genome editing and immunomodulation to treat two major causes of severe sight impairment: age-related macular degeneration (AMD) and non- infectious uveitis. While the pathogenesis of dry AMD remains uncertain, there is evidence to suggest that amyloid-β, a toxic peptide resulting from alternative cleavage of amyloid precursor protein (APP), may play a central role in linking various known risk factors and initiating innate immune responses that lead to retinal pigment epithelial (RPE) degeneration. To test this hypothesis, we will use an AAV-delivered CRISPR/Cas9 vector to disrupt APP gene in the retina and test its effects on AMD progression and amyloid-β knockdown in mice and non-human primate (NHP) models, respectively. In addition, we will investigate the in vivo genome editing efficacy and innate immune responses to CRISPR guide RNA and Cas9 endonuclease in the NHP retina. Finally, as a novel strategy for controlling chronic intraocular inflammation in uveitis, we will test whether AAV-mediated expression of a key T-cell immune checkpoint regulator could suppress retinal inflammation in a mouse model of uveitis.