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.

项目摘要 GM1神经节病是溶酶体储存疾病，其中关键水解酶（称为β-）溶酶体中缺少半乳糖苷酶，导致称为复杂糖的有毒积累神经节，特别是GM1和GA1主要在中枢神经系统中。目前没有治愈方法或有效的治疗方法。治疗相关疾病类型的主要方法涉及替换通过注射到循环中缺失的酶。尽管静脉酶替代疗法（ERT）解决该疾病的许多方面，不幸的是，它无法解决该疾病的并发症虽然，ERT不能治愈这种疾病，它可能会对患者的发育产生明显影响因此生活质量。静脉内ERT已成功商业化用于溶酶体市场上有批准的药物，包括（i）MPS的LARONIDASE I（Aldurazyme®，Alpha-Iduronidase，Hurler综合征），（ii）MPS II的IDurrSulfatase（Elaprase®，Iduronate-2-- MPS VII（MEPSEVII™，β-葡萄糖醛酸酶，狡猾的），硫酸酶，猎人综合征）和（iii）vesronidase alfa 综合征）。脑室内（ICV）ERT也已成功商业化了用于进行性的神经退行性溶酶体疾病称为棕褐色疾病。 cerliponase alfa（Brineura®，三肽基肽酶-1）是一种直接通过ICV输注到大脑的溶酶体酶以替换默认酶。该疗法是第一个安全有效的ICV ERT，该疗法已批准直接输送到大脑。一个阶段 II临床试验也使用了直接传递到大脑的改良溶酶体ICV。 FDA和投资者在一起熟悉ERT及其商业化路径，这两者都对于进行临床试验至关重要。该提议着重于ICV路线的发展管理直接对中枢神经系统执行ERT及其用于治疗GM1的应用神经节病。 GM1神经节病具有严重的神经退行性符号，没有当前疗法由于在血脑屏障上的运输不良而可用。在我们的研究中，我们将设计细胞以生产足够数量的重组人β-半乳糖苷酶用于GM1神经节病淘汰老鼠。这些小鼠将是ICV管理的酶，并分析剂量依赖性生物分布将评估酶以及对生化和组织理学病理学的影响。有效和安全将以单性间歇性剂量进行评估；每周一次，持续8周的剂量研究。结果将提供需要进行临床前信息，以对人类对这种疾病进行新的治疗。