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.

项目摘要 直到最近，还没有有效的治疗视网膜变性的方法。FDA批准Luxturna， 第一个针对RPE 65中双等位基因突变的基因疗法，为更广泛的应用开辟了领域。 视网膜疾病快速增长的临床试验和新兴公司的数量反映了这一影响 成功，并表明对视网膜基因治疗的高期望。然而，非常需要 为许多剩余形式的视网膜变性开发新的方法，如RPE 65相关的营养不良 只影响一小部分患者。此外，所用载体和手术方法的组合 对于这种疾病，靶向视网膜中具有显著结构改变的中央凹是次优的。主要 必须解决的障碍，以改善临床结果并将基因疗法的应用扩展到 在不同疾病阶段的许多视网膜病是：1）有效的载体递送至中央视网膜， 损害剩余的光感受器，这是视网膜下注射在条件下的一个重要的、有记录的问题， 在视网膜结构受损的情况下，2）有效地将基因递送靶向受影响的细胞，特别是 视网膜上的光感受器和RPE，以及3）限制与 玻璃体内注射这些问题与所有当前和未来的视网膜基因治疗计划有关。在这里， 我们通过开发一种创新的视网膜前基因治疗方法来解决这些障碍 对于NPHP 5-LCA和RPE 65-LCA 2，我们的团队开发了一种新型的生物相容性视网膜粘附凝胶， 直接向视网膜释放高效的AAV。我们创造了全面高效的发展 一个允许快速翻译的计划，利用专家团队的互补技能， 成功的翻译发展记录。我们将进一步开发可调的生物相容性凝胶， 注射系统将这些载体直接输送到视网膜，我们将在 植入物允许载体释放的方向性以提高效率。我们将决定最有效的 利用我们最近开发的单细胞移植相容性感光细胞和RPE靶向AAV载体 RNA-Seq范例。我们将在两个经过充分研究的自然发生的 主要影响光感受器（NPHP 5-LCA）和RPE（RPE 65-LCA 2）的LCA犬模型，我们 将表征免疫反应和毒性。本文所开发的创新方法将产生一种新的 用于直接、非侵入性和有效的AAV递送至视网膜的平台，减少扩散和所需剂量 以及相关的免疫反应。这种新的基因递送平台直接适用于所有外部 视网膜疾病的目标，铺平了道路，为更安全，更有效和有针对性的方法，以治疗广泛的 一系列的疾病