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REVIEW article

Front. Immunol.

Sec. Immunological Tolerance and Regulation

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1664968

Immune responses in retinal gene therapy: challenges, mechanisms, and future strategies

Provisionally accepted
  • Wuhan University People's Hospital Eye Center, Wuhan, China

The final, formatted version of the article will be published soon.

Retinal gene therapy has advanced significantly, offering potential treatments for inherited retinal diseases (IRDs) such as retinitis pigmentosa, which previously lacked effective interventions. Central to this progress are adeno-associated virus (AAV)-based delivery systems, which have become the primary platform for ocular gene therapy due to their favorable safety profile, ability to target specific retinal cell types, and long-lasting therapeutic effects. However, accumulating evidence reveals that even "immune-privileged" retinal microenvironments are not exempt from immune challenges, affecting both the safety and efficacy of these therapies. Both innate immune pathways and adaptive responses can induce intraocular inflammation, leading to reduced transgene expression and compromised treatment. Understanding how these immune mechanisms interact with therapeutic outcomes is crucial for developing effective intervention strategies. This review examines evidence from both animal models and human trials to explore how immune activation affects treatment efficacy across various delivery methods and vector designs. We also assess emerging strategies aimed at protecting retinal function while reducing systemic toxicity.

Keywords: retinal gene therapy, Immune responses, Inherited retinal diseases, adeno-associated virus (AAV), Immunomodulation

Received: 13 Jul 2025; Accepted: 01 Oct 2025.

Copyright: © 2025 Ma and Shen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Yin Shen, yinshen@whu.edu.cn

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