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

基本信息

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
项目类别：
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

项目摘要

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 GM1 和 GA1 主要作用于中枢神经系统，目前尚无治愈方法或方法。治疗相关类型疾病的主要方法是替代治疗。通过静脉注射酶替代疗法（ERT）将缺失的酶注射到循环中。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。因此，静脉 ERT 已成功商业化用于溶酶体治疗。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）脑室 (ICV) ERT 也已成功商业化用于渐进性治疗。神经退行性溶酶体疾病，称为 Batten 病。肽酶-1) 是一种溶酶体递送酶，通过 ICV 直接输注至大脑以替代缺陷该疗法是第一个被批准用于直接输送至大脑的安全有效的 ICV ERT。 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，这两者该提案的重点是 ICV 途径的开发。直接对中枢神经系统进行 ERT 给药及其在治疗 GM1 中的应用 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获得。在我们的研究中，我们将改造细胞来生产。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。以单次间歇剂量进行评估；每周一次，持续 8 周的剂量研究。开发人类疾病的新疗法所需的临床前信息。