AAV.IVT18-mediated RDH12 gene therapy restores retinal metabolism in Rdh12 knockout rats and patient-derived iPSC-retinal organoids

Biallelic variants in retinol dehydrogenase 12 ( RDH12 ) cause severe inherited retinal diseases (IRDs) with no available treatments. Given the potential risks of subretinal delivery in patients with macular atrophy, we evaluated intravitreal AAV-mediated RDH12 gene augmentation. A Rdh12 -knockout rat model and patient-derived iPSC retinal organoids (ROs) were established. Reductase activity was assessed by measuring all-trans retinol levels using LC-MS/MS, while accumulation of the toxic aldehyde 4-hydroxynonenal (4-HNE) was quantified by ELISA. Therapeutic AAV.IVT18-hRDH12 was delivered via intravitreal injection in rats and by transduction in ROs. Retinal structure and function were assessed following treatment in rat model. Rdh12 knockout rat retinas showed reduced all-trans retinol production and increased 4-HNE protein adduct levels. Patient-derived ROs developed cyst-like structural changes and showed altered rhodopsin distribution. AAV.IVT18-hRDH12 treatment restored RDH12 expression in both models. All-trans retinol levels increased approximately 11-fold in knockout rat retinas and by 83% in patient-derived ROs, while 4-HNE protein adduct levels decreased by approximately 65% in both models. Retinal structure and electroretinogram responses did not differ between AAV-treated and untreated knockout rats. This study provides preclinical proof-of-concept for intravitreal AAV.IVT18-mediated RDH12 gene augmentation. Treatment increased retinaldehyde reductase activity and reduced 4-HNE accumulation in both models, supporting further evaluation for RDH12 -associated retinal degeneration.