Intravitreal gene therapy for inherited retinal disease

遗传性视网膜疾病的玻璃体内基因治疗

• 批准号: 10660784
• 负责人: ALA MOSHIRI
• 金额: $ 65.35万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660784
• 关键词: Affect; Aftercare; Agonist; Alleles; Animals; Antibodies; Area; Atrophic; Biological Assay; Birth; Blindness; Blood; Blood specimen; Breeding; Bulla; CD8-Positive T-Lymphocytes; California; Capsid; Cell Death; Cells; Child; Circulation; Classification; Clinical; Clinical Trials; Complication; Cone; Cytometry; Diffuse; Diffusion; Directed Molecular Evolution; Disease; Electrophysiology (science); Engineering; Exposure to; Eye; FDA approved; Gene Combinations; Gene Transfer; General Anesthesia; Genes; Genetic; Hand; Homozygote; Immune; Immune system; Immunity; Immunize; Immunohistochemistry; Immunologic Surveillance; Immunosuppression; Inflammation; Inflammatory; Inherited; Injections; Interleukin-10; Macaca; Macaca mulatta; Measures; Mediating; Medicine; Mendelian disorder; Modeling; Mutation; Myelogenous; Myeloid Cell Activation; Operative Surgical Procedures; Outpatients; Patients; Penetration; Persons; Pharmaceutical Preparations; Photoreceptors; Phototransduction; Physiological; Primates; RPE65 protein; Randomized; Reaction; Regimen; Reporting; Research; Retina; Retinal Cone; Retinal Detachment; Retinal Diseases; Retinal macula; Risk; Role; Route; Serotyping; Severities; Site; Source; Specialist; Structure of retinal pigment epithelium; Surgical complication; T cell response; Technology; Testing; Therapeutic; Therapeutic Effect; Therapeutic Studies; Time; Tissues; Transduction Gene; Transgenes; Treatment Efficacy; Triamcinolone; Uveitis; Variant; Viral; Viral Genes; Viral Vector; Virus; Vision; Visual; Vitrectomy; Vitreous humor; adaptive immune response; analog; clinical phenotype; comparative efficacy; cytokine; efficacy evaluation; efficacy testing; fovea centralis; gene induction; gene therapy; improved; intravitreal injection; macula; neutralizing antibody; nonhuman primate; novel; photoreceptor degeneration; prevent; promoter; retinal imaging; seropositive; subretinal injection; therapeutically effective; transduction efficiency; vector; vision science

Project Summary/Abstract Inherited retinal diseases (IRDs) are a major source of blindness worldwide. These diseases are typically single-gene disorders that result in the degeneration of photoreceptor cells. Historically they have been classified based on the clinical phenotype and electrophysiological results, and then grouped into various disease entities. In the past three decades the genetic basis of many forms of inherited retinal diseases have been discovered leading to the identification of over 270 retinal disease genes. Importantly, the field of medicine and vision science has resulted in an FDA-approved viral mediated gene therapy for IRD associated with mutations in RPE65. Children with this condition are treated with AAV carrying RPE65 delivered to the macula in the subretinal space at the time of vitrectomy. Many other single gene disorders affecting the retina are currently being targeted in various clinical trials, mostly through similar strategies to deliver virus to the macula through the subretinal route. Viral mediated gene therapy administered in this fashion is limited by treatment of only the macular area. Furthermore, it requires intraocular surgery, detachment of the macula from the retinal pigmented epithelium, and carries the risk of sight-threatening surgical complications. Recent studies have demonstrated progressive macular atrophy (retinal cell death) at the site of the subretinal bleb in ~15% of patients receiving this gene therapy within the first year after treatment, suggesting subretinal gene therapy may ultimately cause more harm than good. Therapeutic administration via the intravitreal route is much less invasive, takes place in a clinical setting, and can potentially be repeated to achieve maximal therapeutic effect. However, intravitreal viral mediated gene therapy can be associated with increased inflammation. In addition, native AAVs do not penetrate the retinal layers to transduce photoreceptors efficiently. In this study, we will take advantage of non-human primates with a mutation in PDE6C, a key component of phototransduction, causing electrically silent cone photoreceptors. With a proven effective therapeutic AAV-PR1.7-PDE6C vector in hand, we will compare the efficacy of AAV delivered via the subretinal vs intravitreal route to rescue cone function. Furthermore, we will compare inflammatory reaction between these contexts, determine the active components of the immune system, and define the role of pre- existing anti-AAV antibodies in host animals. We will measure the degree to which the route of delivery and inflammation affects the physiologic rescue. This proposal will advance the field of intravitreal gene therapy for inherited retinal diseases. The aims of this proposal will determine the efficacy of intravitreal compared to subretinal gene therapy, the role of pre-existing circulating antibodies in the host that may mitigate the efficacy of treatment, and the degree to which ocular inflammation affects the visual rescue. Together, the aims of this study will advance the understanding of intravitreal gene therapy and its relationship with ocular inflammation and treatment efficacy.

项目摘要/摘要 遗传性视网膜疾病（IRD）是全球失明的主要来源。这些疾病通常是 单基因疾病导致感光细胞变性。从历史上看，他们一直 根据临床表型和电生理结果进行分类，然后分为各种 疾病实体。在过去的三十年中，许多形式的继承视网膜疾病的遗传基础具有 被发现导致鉴定超过270个视网膜疾病基因。重要的是， 医学和视力科学导致了FDA批准的病毒介导的IRD相关的基因疗法 RPE65中的突变。患有这种疾病的儿童用载有RPE65的AAV治疗 玻璃体切除术时视网膜下空间中的黄斑。许多其他影响视网膜的单一基因疾病 目前正在针对各种临床试验，主要是通过类似策略将病毒运送到 黄斑穿过视网膜下路线。以这种方式进行的病毒介导的基因疗法受到限制 仅处理黄斑区域。此外，它需要眼内手术，黄斑脱离 来自视网膜色素上皮，并具有威胁性手术并发症的风险。最近的 研究表明，在视网膜下Bleb的部位进行性黄斑萎缩（视网膜细胞死亡） 在治疗后的第一年接受这种基因治疗的患者中，约有15％表明视网膜下基因 治疗最终可能造成的弊大于利。通过玻璃室内路线的治疗性给药是 侵入性少得多，发生在临床环境中，并有可能重复以达到最大 治疗效果。但是，玻璃室内病毒介导的基因治疗可能与增加有关 炎。此外，天然AAV不会穿透视网膜层转导光感受器 有效。在这项研究中，我们将利用具有PDE6C突变的非人类灵长类动物（键） 光转导的成分，导致电静音锥光受体。有效 治疗性AAV-PR1.7-PDE6C向量，我们将比较通过该AAV的功效 视网膜下与玻璃室内途径挽救锥功能。此外，我们将比较炎症反应 在这些环境之间，确定免疫系统的活性成分，并定义了前pre的作用 宿主动物中现有的抗AAV抗体。我们将衡量交付途径和 炎症会影响生理救援。该建议将推进玻璃体内基因治疗领域 继承的视网膜疾病。该提案的目的将决定与 视网膜下基因疗法，宿主中现有循环抗体的作用可能会缓解功效 治疗以及眼部炎症影响视觉救援的程度。在一起的目的 研究将提高对玻璃体内基因疗法及其与眼部炎症的关系的理解 和治疗功效。