An HSV-1-Based Vector Platform for Localized Delivery to the Posterior of the Eye

Abstract

Purpose : Clinical use of a herpes simplex virus type 1 (HSV-1)-based gene therapy vector, beremagene geperpavec (B-VEC), has been successful in treating skin- and eye-related pathologies associated with dystrophic epidermolysis bullosa (Guide, NEJM 2022; Sabater, ARVO 2023). The underlying platform technology is now being explored for its potential in treating genetic disorders affecting the eye, necessitating determination of feasible routes for safe transgene delivery, particularly to the posterior of the eye.

Methods : The ocular distribution and retinal cell-type affinity of a fluorescent reporter virus was evaluated in wild-type mice following one time vector administration via three injection techniques (suprachoroidal, subretinal, and intravitreal; Fig. 1), representing accepted intraocular delivery methods for current therapeutics. Vector cell-type affinity in the retina was assessed via co-staining of viral mCherry (mCh) expression and markers of rhodopsin (photoreceptor marker) or retinoid isomerohydrolase (retinal pigment epithelial cell (RPEC) marker). Hematoxylin and eosin staining was used to observe inflammatory cell infiltration. Vector genome dissemination was assessed by quantitative PCR (qPCR) as a measure of biodistribution.

Results : Suprachoroidal and subretinal injections resulted in disseminated mCh expression across the retina, specifically in photoreceptors and RPECs. Intravitreal injection revealed mCh signal in the cornea, iris, and ciliary body. Very few inflammatory cells were observed in the suprachoroidal and subretinal groups, while the intravitreal group showed mild inflammatory cell infiltration. qPCR of murine plasma revealed low-detectable levels of vector genomes after subretinal injection; no significant dissemination was detected after intravitreal or suprachoroidal treatment.

Conclusions : The HSV-1-based vector platform can transduce multiple clinically-relevant cell types in the eye, including both photoreceptors and RPECs in the retina, with little-to-no inflammation, supporting further development of this technology for ocular disorders, particularly inherited retinal diseases.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

Figure 1. Routes of murine ocular administration for an HSV-1-based fluorescent reporter vector (HSV-1-mCh). Created using BioRender.