Combined intraocular and intravenous gene delivery for therapy of gyrate atrophy of the choroid and retina

: Gyrate atrophy of the choroid and retina (GACR) is due to ornithine aminotransferase (OAT) deficiency, which causes hyperornithinemia, leading to retinal pigment epithelium, followed by choroidal and retinal degeneration. Adeno-associated virus serotype 8 (AAV8) vector-mediated OAT (AAV8-OAT) liver gene transfer reduces ornithinemia in the Oat-/- mouse model of GACR and improves retinal function and structure. Since OAT is expressed in various tissues including the retina, we investigated the efficacy of restoration of OAT expression in either retina or liver or both tissues on the retinal phenotype of Oat-/- mice. Intravenous and subretinal administration of AAV8-OAT resulted in intraocular and liver OAT expression with reduced ornithinemia after intravenous AAV8-OAT administration, while intraocular ornithine levels were significantly reduced only following combined gene delivery. Accordingly, only Oat-/- animals treated with combined intravenous and subretinal AAV8-OAT administrations showed significant improvements in both retinal morphology and function. This work shows the benefits of combined liver and retinal OAT supplementation for the treatment of GACR.