Abstract
Purpose :
We recently demonstrated that split intein-mediated protein trans-splicing can expand AAV transfer capacity and enable the efficient reconstitution of the large ATP-binding cassette subfamily A member 4 (ABCA4) which is defective in Stargardt disease (STGD1), the most common form of inherited macular degeneration.
Starting from this observation, we showed that subretinal administrations of AAV.ABCA4.intein vectors improves the phenotype of a STGD1 mouse model.
We wanted to further evaluate the translational potential of AAV.ABCA4.intein.
Methods :
A 13-week long non-GLP, toxicokinetic, ocular safety and expression study was conducted in non-human primates (NHPs) of AAV.ABCA4.intein vectors. NHPs received a sub-retinal injection of either vehicle (control, CTR) or AAV.ABCA4.intein vectors at one of two relevant doses, as well as a unique anti-inflammatory regimen.
Results :
Ocular inflammation showed a dose-dependent severity, gradually decreasing over time. Anterior inflammation disappeared by week 5, while vitreous cells returned to control levels by week 9 in most eyes.
Electroretinography indicated a mild, dose-dependent reduction in amplitude at week 5, with no abnormalities observed by the study end, except for a borderline reduction in one eye treated at the high dose. Histopathological examination revealed minimal ocular findings, mainly focal and localized to the dosing site, and improving over time. Ocular imaging corroborated these findings.
BaseScope analysis showed nearly total photoreceptor co-expression of mRNAs encoding both ABCA4.intein halves across an extended retinal region, supporting AAV intein potential for human translation.
Conclusions :
Our data demonstrate that AAV.ABCA4.intein vectors can be administered safely to NHPs under an immunosuppressive protocol designed for use in man, and at doses demonstrating robust expression of both mRNA halves, matching the pattern of endogenous ABCA4. In conjunction with data showing efficacy in animals, this AAV.ABCA4.intein product shows potential to treat retinal dystrophies, such as Stargardt Disease, using a similar approach.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.