ORIGINAL RESEARCH article
Front. Med.
Sec. Gene and Cell Therapy
Volume 12 - 2025 | doi: 10.3389/fmed.2025.1679619
This article is part of the Research TopicNext-Generation Gene and Cell Therapies: Targeting Diseases at Their OriginView all articles
Preclinical Biodistribution and Toxicology Assessment of an AAV5-Based Subretinal Modifier Gene Therapy for Retinitis Pigmentosa
Provisionally accepted
- Ocugen, Inc., Malvern, United States
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Retinitis pigmentosa (RP) is a multifactorial disease caused by mutations in over 100 genes affecting ~1 in 4000 people worldwide and is characterized by abnormalities in rod and cone photoreceptors. Gene therapy approaches are promising and have been established to provide an unprecedented treatment option for genetic diseases caused by mutation(s) in a single gene. However, traditional gene therapy approaches are not pragmatic for RP due to its heterogeneous genetic background. To this end, modifier gene therapy is the unique approach in which a transgene can correct or rescue the detrimental effects caused by mutations in unrelated gene(s). NR2E3 (Nuclear receptor subfamily 2 group E member 3) is a nuclear hormone receptor that exhibits the characteristics of a modifier gene. In preclinical studies, subretinal delivery of NR2E3 rescued the RP phenotype by resetting the molecular pathways to restore normal ocular structure and function in multiple RP disease models. For clinical studies, AAV5-hNR2E3 was designed for subretinal delivery of the hNR2E3 gene through the AAV5 vector in RP patients. In this study, we evaluated the safety and biodistribution (delivery and expression) of a gene therapy candidate, OCU400 (AAV5-hNR2E3) in Göttingen minipigs delivered via the subretinal route. Administration of the product at all dose levels was well tolerated and resulted in ocular changes that were minor and mostly related to the dosing procedure with no significant signs of systemic and ocular toxicity. AAV5-hNR2E3 vector was preferentially localized to the target retinal tissues with minimal to no exposure to systemic organs and tissues after subretinal administration. This localized delivery efficiently transduced retinal cells where delivered transgene produced NR2E3 protein.
Keywords: Retinitis Pigmentosa, Modifier Gene Therapy, nuclear hormone receptor, hNR2E3, Subretinal delivery
Received: 04 Aug 2025; Accepted: 02 Oct 2025.
Copyright: © 2025 Upadhyay, Drag, Singh, Rajanala and Arumugham. 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: Arun K Upadhyay, arun@ocugen.com
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