Abstract
Purpose :
There are no treatments that can attenuate further loss in retinal pigment epithelium (RPE) cells and photoreceptors (PR) associated with geographic atrophy (GA). Whilst experimental anti-complement treatments display moderate success in slowing GA progression, there is an unmet need for therapeutics that do not raise the risk of neovascularisation whilst providing greater efficacy. We have developed a bi-cistronic gene therapy, IKC159V, which expresses a soluble membrane regulatory protein (sCD46) to reduce complement attack, and pigment epithelium-derived growth factor (PEDF) to protect the RPE and PR cells from oxidative stress.
Methods :
IKC159V was evaluated in multiple rodent GA models. Protein expression levels were examined by retinal immunohistochemistry and vitreal ELISA or Western blot after intravitreal or subretinal delivery. Efficacy was evaluated via fluorescein angiography and choroidal flatmount analysis 7 days post laser CNV. Functional activity of sCD46 was determined through vitreal C3b cleavage assays and PEDF retino-protection was demonstrated 7-days after intravitreal NMDA-induced toxicity or 2-days after intravenous sodium iodate (SI) treatment.
Results :
Eyes treated with IKC159V showed significantly elevated levels of sCD46 and PEDF in the vitreous from 3 weeks post-delivery. The activity of sCD46 resulted in significantly more cleavage of C3b to iC3b (IKC159V= 47%, Null= 8%, p ≤ 0.0001) and was as efficacious as a vector expressing CFI only (CFI= 59%). In the mouse SI model which exhibits the loss of both RPE and PR, common with GA, IKC159V was able to show significant RPE sparing following systemic SI measured 2 days later (IKC159V= 44% RPE loss, Null= 71%, p ≤ 0.0001). In the laser CNV model, IKC159V reduced the severe leakage scores (2a+2b) by 50% compared to the Null vector. Finally, elevated PEDF levels correlated with retinal ganglion cell neuroprotection from 30nmol NMDA insult (IKC159V= 780 cells, Null= 358 cells, p ≤ 0.001).
Conclusions :
IKC159V leads to the expression of functionally active sCD46 and PEDF that show a reduction in both the activation of the complement cascade and protection of retinal cells respectively. Importantly, our data suggest that expression of PEDF in combination with sCD46 may slow GA progression and reduce VEGF-induced leakage in addition to neovascularization. These data support the therapeutic potential of IKC159V for the treatment of GA.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.