Abstract
Purpose :
Even though VEGF inhibition is effective, there is a crucial need for longer-acting anti-VEGF agents to reduce the burden of repeated IVT injections and alternative therapeutic approaches to improve outcomes in wet AMD patients. Here, we evaluate a non-viral gene therapy approach to deliver aflibercept, a potent anti-VEGF inhibitor, or Decorin (DCN), an endogenous TGF-beta inhibitor with known anti-angiogenic and anti-fibrotic properties, to reduce choroidal neovascularization (CNV) in rats. Finally, we designed EYS809, a dual-gene plasmid, to deliver sustained concentrations of both proteins.
Methods :
Aflibercept- or DCN-coding plasmids (30 µg/eye) were electrotransfered in the rat ciliary muscle 3 days prior laser-induced CNV. IVT injection of a human equivalent dose of aflibercept (15 mg/eye) or recombinant DCN (1 mg/eye) at disease induction served as positive controls, respectively. CNV leakage was assessed by fluorescein angiography (FA). Different dual gene expression cassettes delivering intraocular concentrations of aflibercept and DCN in rats were compared.
Results :
Electrotransfection of plasmids resulted in sustained intravitreal production of aflibercept or DCN in the vitreous during the 2 week-study while aflibercept or DCN were quickly eliminated following IVT. Following both plasmid or IVT administration aflibercept reduced incidence of Grade 3 CNV lesions to 11% and 29%, respectively, vs. 59% in untreated rats. The percentage of eyes with at least one clinically relevant lesion was also reduced in both treatment groups (39% and 63%, respectively vs. 97% in untreated). Similarly, plasmid- or IVT-administered DCN reduced the incidence of Grade 3 CNV lesions to 36% and 24%, respectively vs. 59% in untreated rats with 60% and 66% of eyes having at least one clinically relevant lesion compared to 75% in untreated rats. The dual gene expression cassette expressing the highest concentrations of both proteins in rat pharmacokinetic assessments was designated as EYS809.
Conclusions :
Our non-viral gene therapy sustained drug delivery approach to deliver anti-VEGF proteins to the eye could be a viable alternative to repeated IVT injections that have been associated with poor visual outcomes in wet AMD patients. The combined effect of aflibercept and DCN, expressed from the EYS809 dual-gene plasmid, is expected to provide benefits over aflibercept alone by also reducing CNV and subretinal fibrosis.
This is a 2021 ARVO Annual Meeting abstract.