Gene therapy for alpha-mannosidosis

描述(申请人提供)：多年来，血脑屏障一直被认为是溶酶体储存疾病系统治疗到达中枢神经系统的主要障碍。然而，最近的数据表明，血清中高水平的β-葡萄糖醛酸苷酶可以改变成年粘多糖病VII小鼠的中枢神经系统损害和行为异常。但问题仍然存在，这种观察结果是否仅限于小鼠和粘多糖病II型，或者是否适用于作为儿童模型的大型动物和其他溶酶体储存性疾病？这项拨款提案旨在回答这些问题。在新生犬静脉注射逆转录病毒基因治疗后，分别持续高血清α-L艾杜糖苷酶和β-葡萄糖醛酸酶水平的粘多糖病I和VII型犬的中枢神经病理损害得到改善。然而，由于粘多糖症犬缺乏中枢神经系统损害的临床体征，无法评估大型动物神经功能的改善。这项赠款申请建议测试与通过血脑屏障相关的血清活性水平，使用体细胞(基于肝脏的)基因疗法治疗患有阿尔法甘露糖症的猫。阿尔法甘露糖症猫有明显的神经学疾病迹象，如果不治疗，会在六个月大时死亡，并且有很好的神经病理损害。阿尔法-甘露糖症猫也被证明对骨髓移植和直接脑内注射病毒载体有反应，所以高血清酶活性是否成功将是明确的。因此，我们建议确定高恒定的血清α-甘露糖苷酶活性是否会跨越血脑屏障，消除临床和神经病理疾病。在提出基因治疗临床试验之前，这是一个重要的原则证据，可以在儿童中发现的60%具有中枢神经系统损害的溶酶体储存疾病中的任何一种产生高血清酶活性。 公共卫生相关性：这笔赠款建议通过使用基因疗法来治疗患有自然发生的遗传储存疾病--阿尔法甘露糖症的幼猫。其目标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。

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.