Non-viral gene therapy eases treatment burden in wet AMD

Reviewed by Elise Orhan, PhD, and Thierry Bordet, PhD

A non-viral gene therapy sustained drug-delivery product (EYS809, Eyevensys) that delivers anti-vascular endothelial growth factor (VEGF) to the eye may replace the need for repeated intravitreal anti-VEGF injections and improve vision in patients diagnosed with wet age-related macular degeneration (AMD).

This real-world approach would both address the tremendous treatment burden imposed on patients with wet AMD by providing an effective longer acting treatment and a non-VEGF-based therapy for patients who need a more convenient treatment approach to control disease progression long term and to achieve improved vision.

The science

This platform is based on the electrotransfection of DNA plasmids that turns the ciliary muscle into a production site for the intraocular expression and secretion of therapeutic proteins, according to Elise Orhan, PhD, the preclinical project leader at Eyevensys.

EYS809 is a dual-gene plasmid designed to deliver sustained concentrations of both the anti-VEGF inhibitor aflibercept (Eylea, Regeneron Pharmaceuticals) and decorin, an endogenous transforming growth factor-beta inhibitor with known anti-angiogenic and anti-fibrotic properties, that has been demonstrated to reduce choroidal neovascularization (CNV) in the rat laser CNV model.

According to Thierry Bordet, PhD, senior author and chief scientific officer of Eyevensys, Decorin has the potential to enhance the efficacy of anti-VEGF therapy by reducing CNV leakage and scarring via non-VEGF dependent pathways.

During the study, aflibercept or decorin-coding plasmids (30 µg/eye) were electrotransfered in the rat ciliary muscle 3 days before laser was applied to induce CNV. Intravitreal injection of a human equivalent dose of aflibercept (15 µg/eye) or recombinant decorin (1 µg/eye) at the CNV induction served as positive controls. Fluorescein angiography (FA) was performed on day 14 to assess the CNV leakage. Different dual gene expression cassettes were compared in rats to deliver optimal intraocular concentrations of the 2 treatments.

Results

“Electrotransfection of plasmids resulted in sustained intravitreal production of aflibercept or decorin in the vitreous during the 2-week study compared with rapid elimination of the 2 therapies after intravitreal injections,” investigators said.

Both plasmid and intravitreal aflibercept reduced the incidence of grade 3 CNV lesions to 11% and 29%, respectively, compared with 59% in untreated rats. The percentage of eyes with at least 1 clinically relevant lesion also decreased in both treatment groups (39% and 63%, respectively compared to 97% in untreated).

In a like manner, plasmid- or intravitreally administered decorin reduced the incidence of grade 3 CNV lesions to 36% and 24%, respectively, compared to 59% in untreated rats with 60% and 66% of eyes having at least one clinically relevant lesion compared to 75% in untreated rats.

Eyevensys previously demonstrated the safety of its platform with a plasmid coding for an anti-tumor necrosis factor protein tested in 18 patients with non-infectious uveitis. The most common adverse event was mild subconjunctival hemorrhage that last for a short period.

Compared with viral gene therapy, the advantages of EYS809 for treating wet AMD include no need for subretinal surgery, easy delivery, the lack of immunogenicity related to the vector, the possibility of repeated dosing to extend treatment effect if needed, and no limited cargo capacity allowing for the delivery of 2 therapeutic proteins. Moreover, EYS809 only transfects the ciliary muscle cells in contrast to potentially any cell in the eye being transfected following intravitreal injection of viral vectors offering a limited risk of retinal damage.

“This non-viral gene therapy sustained drug delivery approach to deliver anti-VEGF proteins to the eye could be a viable alternative to repeated intravitreal injections that have been associated with poor visual outcomes in patients with wet AMD,” investigators concluded. “The combined effect of aflibercept and decorin, expressed from the EYS809 dual-gene plasmid, is expected to provide benefits over aflibercept alone by also reducing CNV and subretinal fibrosis.”

Elsie Orhan, PhD

E: Elise.orhan@eyevensys.com

This article is adapted from Orhan’s presentation at the Association for Research in Vision and Ophthalmology’s 2021 virtual annual meeting. Orhan is an employee of Eyevensys.

Thierry Bordet, PhD

E: Thierry.bordet@eyevensys.com

Bordet is an employee of Eyevensys.