Title: Development and Validation of Therapy for GM1 Gangliosidosis

标题：GM1 神经节苷脂沉积症疗法的开发和验证

• 批准号: 10678309
• 负责人: Jillian R Brown
• 金额: $ 46.17万
• 依托单位: TEGA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10678309
• 关键词: 5 year old; Adolescent; Adult; Animal Model; Beta-glucuronidase; Bilateral; Biochemical; Biodistribution; Biological Assay; Blood - brain barrier anatomy; Bolus Infusion; Bone Marrow; Brain; Bypass; CNS degeneration; Catheters; Cell Line; Cells; Central Nervous System; Cerebral Ventricles; Cessation of life; Child; Childhood; Chinese Hamster Ovary Cell; Chronic; Circulation; Clinical Trials; Complex; Development; Developmental Delay Disorders; Dihydrofolate Reductase; Disease; Disease Progression; Dose; Dysplasia; Engineering; Enzyme Tests; Enzymes; Exhibits; Fibroblasts; Functional disorder; GLB1 gene; Galactose; Ganglioside GM1; Gangliosides; Gangliosidosis GM1; Gene Amplification; Genetic Diseases; Goals; Heart; Hip region structure; Histologic; Human; Hydrolase; Implant; In Vitro; Infusion procedures; Injections; Intravenous; Intravenous infusion procedures; Knockout Mice; L-Iduronidase; Life; Link; Literature; Liver; Lysosomal Storage Diseases; Lysosomes; Marketing; Measures; Methods; Methotrexate; Morbidity - disease rate; Motor Skills; Mucopolysaccharidoses; Mucopolysaccharidosis I; Mucopolysaccharidosis I H; Mucopolysaccharidosis II; Mucopolysaccharidosis VII; Mus; Mutation; Nerve Degeneration; Neurocognitive Deficit; Neurologic Symptoms; Neurons; Ommaya Reservoir; Operative Surgical Procedures; Pathology; Patients; Penetration; Pharmaceutical Preparations; Phase II Clinical Trials; Polysaccharides; Preparation; Probability; Process; Production; Quality of life; Recombinants; Reporting; Research; Residual state; Route; Safety; Scalp structure; Seizures; Spielmeyer-Vogt Disease; Symptoms; Testing; Therapeutic; Therapy Clinical Trials; Tissues; Validation; Western Blotting; autosome; behavioral study; beta-Galactosidase; blood-brain barrier crossing; bone; clinical phenotype; clinical trials in animals; commercialization; effective therapy; enzyme activity; enzyme deficiency; enzyme replacement therapy; iduronate-2-sulfatase; in vitro activity; infancy; mutant; neuropathology; novel; pre-clinical; preclinical study; premature; prevent; progressive neurodegeneration; recessive genetic trait; restoration; scoliosis; success; sugar; therapeutic enzyme; tripeptidyl aminopeptidase; uptake

PROJECT SUMMARY GM1 gangliosidosis is lysosomal storage disease in which a key hydrolase enzyme, known as beta- galactosidase is missing in the lysosome resulting in the toxic accumulation of complex sugars called gangliosides, in particular GM1 and GA1 principally in the central nervous system. There is currently no cure or effective treatment available. A primary approach for treating related types of disorders involves replacement of the missing enzyme by injection into the circulation. Although intravenous enzyme replacement therapy (ERT) resolves many aspects of the disease, unfortunately it does not resolve complications of the disease in the CNS. Although, ERT is not a cure for this disease it can have a marked effect on the patient’s development and thus quality of life. Intravenous ERT has been successfully commercialized for lysosomal mucopolysaccharidoses (MPS) disorders with approved drugs on the market, including (i) Laronidase for MPS I (Aldurazyme®, alpha-iduronidase, Hurler Syndrome), (ii) Idursulfatase for MPS II (Elaprase®, iduronate-2- sulfatase, Hunter Syndrome) and (iii) Vestronidase alfa for MPS VII (Mepsevii™, beta-glucuronidase, Sly Syndrome). Intracerebroventricular (ICV) ERT has also been successfully commercialized for a progressive neurodegenerative lysosomal disease called Batten disease. Cerliponase Alfa (Brineura®, tripeptidyl peptidase-1) is a lysosomal enzyme delivered via ICV infusion directly to the brain to replace the deficient enzyme. This therapy is the first safe and effective ICV ERT approved for direct delivery to the brain. A Phase II clinical trial is also underway using a modified lysosomal enzyme ICV-delivered directly to the brain. Together, the FDA and investors are familiar with ERT and its commercialization path forward, both of which are essential in reaching a clinical trial. This proposal focuses on the development of the ICV route of administration to perform ERT directly to the central nervous system and its application to treating GM1 gangliosidosis. GM1 gangliosidosis has severe neurodegenerative symptoms with no current therapies available due to poor transport across the blood-brain barrier. In our studies, we will engineer cells to produce sufficient quantities of recombinant human beta-galactosidase enzyme for testing in GM1 gangliosidosis knockout mice. These mice will be ICV-administered enzyme and analyzed for dose-dependent biodistribution of the enzyme and effects on biochemical and histological pathology will be evaluated. Efficacy and safety will be assessed in single intermittent dose; once a week for 8 weeks dosing study. The results will provide the preclinical information needed to proceed towards a novel treatment of the disease in humans.

项目概要 GM1 神经节苷脂贮积症是一种溶酶体贮积病，其中一种关键的水解酶（称为 β- 溶酶体中缺少半乳糖苷酶，导致称为复合糖的有毒积累 神经节苷脂，特别是主要存在于中枢神经系统中的GM1和GA1。目前尚无治愈方法或 可获得有效的治疗。治疗相关类型疾病的主要方法包括替代 通过注射到循环中来补充缺失的酶。尽管静脉酶替代疗法（ERT） 解决了该疾病的许多方面，不幸的是它并不能解决该疾病的并发症 中枢神经系统。虽然 ERT 不能治愈这种疾病，但它可以对患者的发育产生显着影响 从而提高生活质量。静脉ERT已成功商业化用于治疗溶酶体 粘多糖贮积症 (MPS) 疾病与市场上批准的药物有关，包括 (i) 用于 MPS 的 Laronidase I（Aldurazyme®，α-艾杜糖醛酸酶，Hurler 综合征），(ii) 用于 MPS II 的艾杜硫酸酯酶（Elaprase®，艾杜糖醛酸-2- 硫酸酯酶、亨特综合症）和 (iii) 用于 MPS VII 的 Vestronidase alfa（Mepsevii™、β-葡萄糖醛酸酶、Sly） 综合症）。脑室内 (ICV) ERT 也已成功商业化，用于渐进式治疗 神经退行性溶酶体疾病称为巴顿病。 Cerliponase Alfa（Brineura®，三肽基 肽酶-1) 是一种溶酶体酶，通过 ICV 输注直接输送到大脑以替代缺陷 酶。该疗法是第一个被批准用于直接递送至大脑的安全有效的 ICV ERT。 A阶段 II 期临床试验也正在进行中，使用一种改良的溶酶体酶 ICV 直接输送到大脑。 FDA 和投资者共同熟悉 ERT 及其商业化道路，这两者 对于进行临床试验至关重要。该提案重点关注智能网联汽车路线的发展 直接对中枢神经系统进行 ERT 给药及其在治疗 GM1 中的应用 神经节苷脂沉积症。 GM1 神经节苷脂沉积症具有严重的神经退行性症状，目前尚无治疗方法 由于穿过血脑屏障的运输不良而无法利用。在我们的研究中，我们将设计细胞来生产 足够量的重组人 β-半乳糖苷酶用于测试 GM1 神经节苷脂沉积症 基因敲除小鼠。这些小鼠将被 ICV 施用酶并分析剂量依赖性生物分布 将评估酶的作用以及对生化和组织病理学的影响。功效和安全性将 以单次间歇剂量进行评估；每周一次，持续 8 周的剂量研究。结果将提供 开发人类疾病的新疗法所需的临床前信息。