Purpose: To provide a review of the current understanding of immunogenicity in AAV-based retinal gene therapy.

Methods: A narrative review of pre-clinical and clinical studies on AAV-based retinal gene therapy focusing on immunogenicity.

Results: A Pubmed search initially identified 387 manuscripts for review. After reading the abstracts, 19 papers were identified as relevant for in depth review. An additional search of clinical-stage programs from key companies was added to the review.

It is generally accepted that a lower dose has a lower risk of immunogenicity, however, finding the right balance between efficacy and risk is challenging. There is a lack of understanding regarding individualized dosing for patients based on factors such as age, disease state, and level of neutralizing antibodies. The mode of delivery, whether subretinal, suprachoroidal, or intravitreal, presents different adaptive and innate cellular immunogenicity profiles. The choice of prophylactic and reactive therapy varies significantly across different clinical trials, making comparisons difficult. Ongoing efforts focus on mitigating the risk of immunogenicity by using different promoters, capsids, adding evading DNA sensors, and developing patient level immunosuppression stragtegies will be discussed.

Conclusion: Despite the FDA approving the first AAV-based retinal gene therapy over 7 years ago, there is still much to learn and understand. Furthermore, the advance of using gene therapy as a biofactory for common retinal diseases, the balance between risk and benefit presents additional challenges.