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 遗传性视网膜疾病是世界范围内导致失明的主要原因。这些疾病通常是 导致感光细胞退化的单基因紊乱。从历史上看，他们一直是 根据临床表型和电生理结果进行分类，然后归类为各种 疾病实体。在过去的三十年里，许多形式的遗传性视网膜疾病的遗传基础 被发现导致了270多个视网膜疾病基因的鉴定。重要的是，这一领域 医学和视觉科学已经为IRD相关患者带来了FDA批准的病毒介导的基因疗法 RPE65基因突变。患有这种情况的儿童使用携带RPE65的AAV进行治疗，该AAV将RPE65运送到 玻璃体切除时视网膜下间隙有黄斑。许多其他影响视网膜的单基因疾病 目前是各种临床试验的靶点，主要是通过类似的策略将病毒传递到 黄斑穿过视网膜下通路。以这种方式实施的病毒介导的基因治疗受到以下限制 仅治疗黄斑区。此外，它还需要眼内手术，黄斑脱离 来自视网膜色素上皮，并带有威胁视力的手术并发症的风险。近期 研究表明视网膜下滤过泡部位的进行性黄斑萎缩(视网膜细胞死亡)。 约15%的患者在治疗后第一年内接受这种基因治疗，提示存在视网膜下基因 治疗最终可能弊大于利。通过玻璃体内途径给药是 侵入性小得多，发生在临床环境中，并有可能重复以达到最大 治疗效果。然而，玻璃体内病毒介导的基因治疗可以与增加 发炎。此外，天然的动静脉动静脉不会穿透视网膜层来转导光感受器。 效率很高。在这项研究中，我们将利用PDE6C突变的非人类灵长类动物，PDE6C是一种关键 光传导的组成部分，导致电静音视锥感光器。具有已被证明有效的 治疗性AAV-PR1.7-PDE6C载体在手，我们将比较AAV通过 视网膜下与玻璃体内途径抢救视锥功能。此外，我们还将比较炎症反应 在这些背景下，确定免疫系统的活性成分，并定义前- 宿主动物中存在抗AAV抗体。我们将在多大程度上衡量交付路线和 炎症影响生理性抢救。这项提议将推动玻璃体内基因治疗领域的发展 遗传性视网膜疾病。这项提案的目的将决定玻璃体内注射的疗效 视网膜下基因治疗，宿主中预先存在的循环抗体的作用，可能会减轻疗效 治疗的好坏，以及眼部炎症影响视力抢救的程度。总而言之，这次会议的目的是 研究将促进对玻璃体内基因治疗及其与眼部炎症的关系的理解 和治疗效果。