Retinal-adhesive thermoresponsive gel for AAV-mediated gene delivery to the outer retina

用于将 AAV 介导的基因传递至外视网膜的视网膜粘附热敏凝胶

• 批准号: 10709508
• 负责人: William A. Beltran
• 金额: $ 71.98万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709508
• 关键词: Address; Adhesives; Adverse effects; Affect; Alleles; Animal Model; Area; Biocompatible Materials; Canis familiaris; Cells; Clinic; Clinical; Clinical Trials; Complex; Data; Dependovirus; Development; Development Plans; Diffusion; Disease; Dose; Engineering; Ensure; Future; Gel; Gene Delivery; Genes; Human; Image; Immune response; Implant; Inflammation; Inflammatory; Injectable; Injections; Leber' s Hereditary Optic Neuropathy; Leber' s amaurosis; Libraries; Marketing; Mediating; Methods; Mutation; Nephronophthisis; Operative Surgical Procedures; Outcome; Outcome Study; Performance; Phenotype; Photoreceptors; Polymers; Procedures; Property; RPE65 protein; Research; Research Personnel; Retina; Retinal Degeneration; Retinal Diseases; Retinal Photoreceptors; Retinal gene therapy; Specificity; Structure of retinal pigment epithelium; Surface; System; Technology; Testing; Therapeutic; Time; Toxic effect; Toxicity Tests; Translations; Validation; Variant; Viral; Viral Vector; Viral load measurement; Virus Diseases; adeno-associated viral vector; biomaterial compatibility; canine model; cell type; ciliopathy; delivery vehicle; disease phenotype; dosage; effective therapy; expectation; fovea centralis; gene augmentation therapy; gene therapy; human model; implant compatibility; improved; in vivo; inherited retinal degeneration; innovation; intravitreal injection; macula; manufacture; member; neuroprotection; next generation; nonhuman primate; novel; novel strategies; optogenetics; particle; patient population; prevent; programs; single-cell RNA sequencing; skills; subretinal injection; success; transgene expression; vector; viscoelasticity

Project summary Until recently, there have been no effective treatments for retinal degenerations. FDA approval of Luxturna, the first gene therapy for bi-allelic mutations in RPE65, has opened the field for application to a broader range of retinal diseases. The rapidly growing number of clinical trials and emerging companies reflect the impact of this success and indicate the high expectations for retinal gene therapy. However, there is a significant need to develop new approaches for the many remaining forms of retinal degenerations, as RPE65-related dystrophies affect a very small population of patients. Moreover, the combination of the vector and surgical approach used for this disease is suboptimal for targeting the fovea in retinas with significant structural alterations. The major obstacles that must be addressed to improve clinical outcomes and extend the application of gene therapies to numerous retinopathies at various disease stages are: 1) efficient vector delivery to the central retina without damaging remaining photoreceptors, a significant, documented concern with sub-retinal injections in conditions where the retina is structurally compromised, 2) efficiently targeting gene delivery to affected cells, especially photoreceptors and RPE across the retina and 3) limiting the inflammatory/immune responses associated with intravitreal injections. These issues are relevant to all current and future retinal gene therapy programs. Here, we address each of these obstacles through development of an innovative new epiretinal gene therapy approach for NPHP5-LCA and RPE65-LCA2, in which a novel, biocompatible, retinal adhesive gel developed by our team releases high efficiency AAVs directly to the retina. We have created a comprehensive and efficient development plan that allows for rapid translation, drawing on the complementary skill sets of a team of experts with a track record of successful translational development. We will further develop the tunable, biocompatible gel and injection system to deliver these vectors directly to the retina, and we will incorporate a backing layer into the implant that allows for directionality of vector release for increased efficiency. We will determine the most efficient implant-compatible photoreceptor and RPE-targeting AAV vectors by utilizing our recently developed single cell RNA-Seq paradigm. We will fully validate this new gene therapy platform in two well-studied naturally occurring canine models of LCA that affect primarily the photoreceptors (NPHP5-LCA) and RPE (RPE65-LCA2), and we will characterize immune response and toxicity. The innovative approach developed herein will result in a new platform for direct, non-invasive and efficient AAV delivery to the retina, reducing diffusion and required dosage as well as the related immune response. This novel gene delivery platform has direct applicability to all outer retinal disease targets, paving the way forward for a safer, more efficient and targeted approach to treat a wide spectrum of disorders.

项目总结