Gene therapy for alpha-mannosidosis

α-甘露糖苷贮积症的基因治疗

• 批准号: 7877550
• 负责人: MARK E HASKINS
• 金额: $ 19.94万
• 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 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7877550
• 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的主要障碍，以达到中枢神经系统的溶酶体储存疾病。然而，最近的数据表明，高血清β-葡萄糖醛酸酶的高度水平可以改变成年粘多糖含量VII小鼠的中枢神经系统病变和行为异常。但是问题仍然存在，这种观察是否仅限于小鼠和粘多含糖VII，还是大型动物作为儿童和其他溶酶体储存疾病的模型是正确的？该赠款提案旨在回答这些问题。在新生儿，静脉内术后基因疗法之后，我们已经显示出具有恒定高血清α-L-二维罗替型酶和β-葡萄糖醛酸糖苷酶的持续高血清α-l-二核苷酶和β-葡萄糖醛酸酶的高血清水平的粘多糖I和VII犬的中枢神经病变病变的改善。但是，由于粘多糖毒犬缺乏中枢神经系统病变的临床迹象，因此无法评估大动物的神经功能的改善。该赠款的应用建议在患有α-甘露术的猫中使用体细胞（基于肝的）基因疗法测试与在血液屏障中过渡相关的血清活性水平。 α-甘露病猫猫具有明显的，有据可查的神经系统疾病迹象，如果未治疗，则死亡六个月，并且描述了良好的神经病理病变。还显示α-甘露病猫对骨髓移植和直接脑注射病毒载体反应，因此很明显，如果高血清酶活性成功。因此，我们建议确定高恒定的血清含量含量含量含量酶的活性是否会越过血脑屏障并消除临床和神经病理学疾病。在提出基因治疗临床试验之前，这是一个重要的原理证明，以在60％的溶酶体储存疾病中的任何一个患有中枢神经系统病变中发现的60％的溶酶体储存疾病中的任何一个。 公共卫生相关性：该赠款建议通过使用基因疗法来治疗天然存在的遗传储存疾病，α-甘露糖苷的猫。目的是在肝脏中产生足够的正常治疗酶，以使其越过血脑屏障并预防或逆转大脑中的疾病。