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Retinal Viral Gene Therapy: Impact of Route of Administration on Serious Adverse Events-A Systematic Review
Aubrey Berger1, Ciera D Johnson2, Alan D Marmorstein3
1Biomedical Graduate Program, Mayo Clinic, Rochester, Minnesota, USA.
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.
Insights
Serious adverse events (SAEs) in retinal viral gene therapy are more common with subretinal injections than intravitreal ones. Consistent patterns across human and animal studies aid safety predictions.
Area of Science:
- Ophthalmology
- Gene Therapy
- Retinal Diseases
Background:
- Retinal viral gene therapy aims to treat vision loss.
- Serious adverse events (SAEs) are a concern in these procedures.
- Understanding SAEs in human and animal models is crucial for safety.
Purpose of the Study:
- To determine the prevalence of SAEs in retinal viral gene therapy.
- To analyze trends in SAEs in human gene therapy surgeries and animal models.
Main Methods:
- A literature review identified relevant human and animal studies.
- Included studies focused on viral gene therapy, subretinal, and intravitreal injections.
- Only studies examining SAEs in clinical trials and post-approval LUXTURNA were considered.
Main Results:
- SAEs occurred in 11.6% of eyes with subretinal vs. 3.2% with intravitreal injections in clinical trials.
- Intravitreal injections had fewer SAEs and less vision loss; inflammation was common.
- Subretinal injections showed higher efficacy but more SAEs, primarily vision loss.
Conclusions:
- Subretinal injections offer higher efficacy but carry greater risks of SAEs compared to intravitreal injections.
- Observed SAE patterns in humans and animals are consistent, suggesting predictive value for safety.
- Optimized delivery, dosing, and monitoring are needed to enhance gene therapy safety and efficacy.
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