Gene therapy for alpha-mannosidosis

α-甘露糖苷贮积症的基因治疗

• 批准号: 8059579
• 负责人: MARK E HASKINS
• 金额: $ 19.72万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8059579
• 关键词: Adult; Adverse effects; Affect; Age; Age-Months; Alpha-mannosidase; Animals; Applications Grants; Behavioral; Beta-glucuronidase; Blood - brain barrier anatomy; Bone Marrow Transplantation; Brain; Canis familiaris; Cessation of life; Child; Clinical; Data; Diagnosis; Disease; Disease Progression; Dose; Electron Microscopy; Enzymes; Felis catus; Gene Transduction Agent; Genetic; Goals; Grant; Hepatic; Histology; Injection of therapeutic agent; Intravenous; L-Iduronidase; Lesion; Liver; Lysosomal Storage Diseases; Magnetic Resonance Imaging; Modeling; Mucopolysaccharidoses; Mucopolysaccharidosis I; Mucopolysaccharidosis VII; Mus; Neonatal; Nervous System Lysosomal Storage Diseases; Nervous System Physiology; Neuraxis; Neurologic; Oligosaccharides; Permeability; Physical Examination; Retroviral Vector; Serum; Systemic Therapy; Testing; Tissues; Viral; Viral Vector; Weaning; alpha Mannosidase B; alpha-Mannosidosis; design; enzyme activity; enzyme replacement therapy; gene therapy; gene therapy clinical trial; normal aging; prevent; public health relevance; therapeutic enzyme; vector

DESCRIPTION (provided by applicant): For many years, the blood brain barrier has been considered a major obstacle to systemic therapy to reach the central nervous system for lysosomal storage diseases. However, recent data have indicated that high serum levels of beta-glucuronidase can alter the central nervous system lesions and behavioral abnormalities in adult mucopolysaccharidosis VII mice. But the question remains, is this observation limited to mice and to mucopolysaccharidosis VII or will it be true for large animals as models for children and for other lysosomal storage diseases? This grant proposal is designed to answer these questions. We have shown improvement in central nervous system neuropathological lesions in mucopolysaccharidosis I and VII dogs with constant high serum levels of alpha-L-iduronidase and beta-glucuronidase, respectively, following neonatal, intravenous retroviral gene therapy. However, because the mucopolysaccharidosis dogs lack clinical signs of the central nervous system lesions, improvement in neurological function in the large animals could not be evaluated. This grant application proposes to test the levels of serum activity associated with transit across the blood brain barrier using somatic (liver-based) gene therapy in cats with alpha-mannosidosis. Alpha-mannosidosis cats have significant, well-documented neurological signs of disease, with death by six months of age if untreated, and well-described neuropathological lesions. Alpha-mannosidosis cats have also been shown to respond to bone marrow transplantation and direct brain injection of a viral vector so it will be clear if high serum enzyme activity is successful. Thus, we propose to determine if high constant serum alpha- mannosidase activity will cross the blood brain barrier and abrogate the clinical and neuropathological disease. This is an important proof of principle before proposing gene therapy clinical trials to produce high serum enzyme activity in any of the 60% of lysosomal storage diseases with central nervous system lesions found in children. PUBLIC HEALTH RELEVANCE: This grant proposes to treat young cats with the naturally occurring genetic storage disease, alpha-mannosidosis, by using gene therapy. The goal is to produce enough normal therapeutic enzyme in the liver to allow it to cross the blood brain barrier and prevent or reverse the disease in the brain.

描述（由申请人提供）：多年来，血脑屏障一直被认为是全身治疗到达溶酶体贮积病中枢神经系统的主要障碍。然而，最近的数据表明，高血清水平的β-葡萄糖醛酸酶可以改变成年粘多糖沉积症VII小鼠的中枢神经系统病变和行为异常。但问题仍然存在，这一观察结果是否仅限于小鼠和粘多糖沉积病VII，或者对于作为儿童和其他溶酶体储存病模型的大型动物也是如此？本研究旨在回答这些问题。我们已经证明，在新生儿静脉内逆转录病毒基因治疗后，具有恒定高血清水平的α-L-艾杜糖醛酸酶和β-葡萄糖醛酸酶的粘多糖样变性I型和VII型犬的中枢神经系统神经病理学病变得到改善。然而，由于粘多糖样变性犬缺乏中枢神经系统病变的临床体征，因此无法评价大型动物的神经功能改善。该资助申请旨在测试与使用体细胞（基于肝脏）基因治疗患有α-甘露糖苷酶病的猫的血脑屏障转运相关的血清活性水平。α-甘露糖苷沉积症猫具有显著的、记录良好的疾病神经学体征，如果不治疗，则在六个月龄时死亡，并且具有描述良好的神经病理学病变。α-甘露糖苷酶病猫也被证明对骨髓移植和直接脑注射病毒载体有反应，因此高血清酶活性是否成功将是清楚的。因此，我们建议确定高恒定血清α-甘露糖苷酶活性是否会穿过血脑屏障并消除临床和神经病理学疾病。这是一个重要的原则证明之前，提出基因治疗临床试验，以产生高血清酶活性的任何60%的溶酶体储存病与中枢神经系统病变的儿童发现。 公共卫生关系：该基金建议通过基因治疗来治疗患有自然发生的遗传性储存疾病α-甘露糖苷沉积症的幼猫。目的是在肝脏中产生足够的正常治疗酶，使其能够穿过血脑屏障，预防或逆转大脑中的疾病。