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. 2025 Aug 21.
doi: 10.1111/ceo.14593. Online ahead of print.

Retinal Viral Gene Therapy: Impact of Route of Administration on Serious Adverse Events-A Systematic Review

Aubrey Berger  1 , Ciera D Johnson  2 , Alan D Marmorstein  3 , Brittni A Scruggs  3
Affiliations

Retinal Viral Gene Therapy: Impact of Route of Administration on Serious Adverse Events-A Systematic Review

Aubrey Berger et al. Clin Exp Ophthalmol. .

Abstract

Background: To explore the prevalence of serious adverse events (SAEs) associated with retinal viral gene therapy and to examine trends influencing SAE occurrences in human gene therapy surgeries and pre-clinical animal trials.

Methods: Literature review was performed to identify peer-reviewed human and animal studies relevant to viral gene therapy, subretinal injections, and intravitreal injections. For clinical trials and post-approval LUXTURNA studies, only those that examined SAEs were included.

Results: Of included clinical trial studies (n = 31), SAEs were recorded in 51 out of 438 eyes (11.6%) that received subretinal injections and in 11 out of 348 eyes (3.2%) that received intravitreal injections. There were fewer intravitreal-related SAEs and less vision loss compared to subretinal gene therapy. Inflammation was the predominant SAE following intravitreal injections, whereas unexplained vision loss was the most common for subretinal injections. Clinical trials utilising subretinal injections met primary or secondary efficacy endpoints more than intravitreal trials. Eighteen studies (429 eyes) of post-approval LUXTURNA were reviewed, and SAEs were reported in 24.7% of eyes, retinal degeneration being most common (20.7%). For 58 animal studies, SAEs were recorded in 17.3% of eyes that received subretinal injections and 8.7% of eyes that received intravitreal injections.

Conclusions: Subretinal injections show higher efficacy than intravitreal injections but are associated with more serious adverse events. Consistent adverse event patterns in humans and large animals highlight their predictive value for safety. There is a need for optimised delivery methods, refined dosing protocols, and improved post-treatment monitoring to improve safety and effectiveness in gene therapy.

Keywords: gene therapy; inherited retinal disease; intravitreal injection; retina; subretinal injection; suprachoroidal injection; viral gene therapy.

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