Abstract
Purpose :
Age-related macular degeneration is a leading cause of blindness worldwide. Current clinically available treatments involve monthly ocular injections that are both burdensome and unpleasant. Gene therapy offers a long-term efficacy solution requiring a one-time injection which leads to stable and dose-dependent therapeutic protein expression. Ocular route of delivery and capsid are important considerations for optimal efficacy, safety and translatability. Here we investigated expression levels and efficacy of AAV8-IKC159V, ikarovec’s lead bicistronic gene therapy expressing PEDF and soluble CD46, in the rodent eye using transcorneal subretinal injections as a surrogate for suprachoroidal clinical delivery.
Methods :
Due to the small size of murine eyes, suprachoroidal delivery is technically not feasible. Therefore, we examined expression using trans-corneal subretinal injections which target a large area of RPEs and minimises vitreous exposure. AAV8-Null vector was compared to AAV8-IKC159V and the expression and function of proteins within the eye evaluated either qualitatively using immunofluorescent imaging of choroidal wholemounts and retinal sections, or quantitatively using vitreal samples and ELISA assays. Laser CNV was used for efficacy readouts and ERGs and fundus imaging for safety.
Results :
Eyes treated subretinally with AAV8-IKC159V showed titre related increases in expression of both proteins, with expression over 10-fold greater than that seen with titre matched AAV2-IKC159V (AAV8 n=15, AAV2 n=7). Function of the AAV8 bicistronic was shown with efficient cleavage of C3b into less active iC3b (increase of 30% breakdown) and a significant reduction in laser CNV leakage area (50% reduction), isolectin lesion size (55% reduction) and MAC (C5b9) area (36% reduction) (n=32-33 lesions) compared to AAV8 Null. Importantly, both vector and delivery had minimal impact on vessel health and retinal function as indicated by ERG and fundus imaging at regular time points out to 6 months post-treatment (106.2µV for Null and 108.1µV for IKC159V).
Conclusions :
Subretinal delivery of AAV8-IKC159V is effective in rodent preclinical models of GA resulting in robust long-term expression of both proteins and with minimal safety flags. These data support the further clinical development of AAV8-IKC159V for the treatment of GA.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.