Abstract
Purpose :
Geographic atrophy has a complex pathophysiology and whilst the recently approved complement targeting therapies provide a much-sought treatment option, there remains an unmet need for therapies with greater efficacy, reduced treatment burden, and without the raised risk of neovascularisation. Our bicistronic AAV vector, IKC159V, expresses a soluble form of a complement co-factor CD46 to reduce pathological complement cascade and pigment epithelium-derived factor (PEDF) to protect RPE and photoreceptors from atrophy and prevent neovascularisation.
Methods :
Null vector, monocistronic PEDF, monocistronic sCD46 and bicistronic PEDF/sCD46 (IKC159V) were examined in a co-culture (HUVEC/human fibroblast) angiogenesis assay, a murine model of laser-induced CNV and a sodium iodate (SI) induced oxidative stress model following intravitreal delivery with an AAV2 capsid.
Results :
In the angiogenesis model, the bicistronic IKC159V and the monocistronic PEDF vectors significantly reduced VEGF-induced angiogenesis (54.6% reduction for IKC159V and 59.3% reduction for monocistronic PEDF) which was not observed by expressing an anti-complement alone. In the laser CNV model, IKC159V significantly reduced both permeability (74% leaky lesions in Null group (n=27) vs 27% leaky lesions in IKC159V (n=29), lesion area (isolectin) and MAC (C5b9) area compared to either of the monocistronic component alone vectors (54.1% reduction for isolectin and 72.8% reduction for MAC). IKC159V also worked more efficaciously than well-known complement-only expressing gene therapies delivered via the same route. In the SI model, the PEDF expressing vector showed significant ERG assessed functional protection from the cytotoxic insult compared to Null vector treated eyes (117.4µV average B wave peak for PEDF group vs 65.10µV for Null vector (n=4-8).
Conclusions :
IKC159V shows greater efficacy in GA disease models than monocistronic vectors expressing anti-complement proteins, or using a factor solely aimed at reducing wAMD conversion or retinal cell preservation. The synergy between PEDF and sCD46 in the IKC159V vector make for a positive next-generation gene therapy for patients with GA.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.