Restoration of central nervous system α-N-acetylglucosaminidase activity and therapeutic benefits in mucopolysaccharidosis IIIB mice by a single intracisternal recombinant adeno-associated viral type 2 vector delivery
Restoration of central nervous system α-N-acetylglucosaminidase activity and therapeutic benefits in mucopolysaccharidosis IIIB mice by a single intracisternal recombinant adeno-associated viral type 2 vector delivery
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DOI：
10.1002/jgm.1480
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发表时间：
2010-07-01
影响因子：
3.5
通讯作者：
McCarty, Douglas M.
中科院分区：
文献类型：
--
作者：
Fu, Haiyan;DiRosario, Julianne;McCarty, Douglas M.
背景寻找有效的中枢神经系统（CNS）递送方法一直是治疗具有全身神经系统表现的疾病的治疗开发面临的主要挑战，例如粘多糖贮积症（MPS）IIIB，一种溶酶体贮积病，由α-N-乙酰氨基葡萄糖苷酶（NaGlu）的常染色体隐性缺陷引起。此前，我们开发了一种方法，即脑池内（i.c.）注射，将重组腺相关病毒（rAAV）载体递送至小鼠的中枢神经系统，从而导致转导广泛的脑室周围分布。方法在本研究中，我们通过脑池内（i.c.）注射将表达人NaGlu的rAAV2载体递送至MPS IIIB小鼠的中枢神经系统。注射方法，以测试其治疗功效和治疗该疾病的神经系统表现的可行性。结果我们证明了单注射液的显着功能神经学益处。成年 MPS IIIB 小鼠的载体输注。该治疗通过介导中枢神经系统中广泛的重组NaGlu表达来减缓疾病进展，从而减少脑溶酶体储存病理学，显着改善认知功能并延长生存期。然而，持续的运动功能缺陷表明中枢神经系统以外区域的病理导致了 MPS IIIB 行为表型。 i.c. 的治疗益处rAAV2 递送具有剂量依赖性，并且可能仅归因于 CNS 转导，因为该过程不会导致体细胞组织中可检测到的转导。结论 单次 IC rAAV2 基因递送在功能上有益于治疗小鼠 MPS IIIB 的 CNS 疾病。它可以立即进行临床转化，有可能改善 MPS IIIB 患者的生活质量。版权所有 (C) 2010 约翰·威利父子有限公司
Background Finding efficient central nervous system (CNS) delivery approaches has been the major challenge facing therapeutic development for treating diseases with global neurological manifestation, such as mucopolysaccharidosis (MPS) IIIB, a lysosomal storage disease, caused by autosomal recessive defect of alpha-N-acetylglucosaminidase (NaGlu). Previously, we developed an approach, intracisternal (i.c.) injection, to deliver recombinant adeno-associated viral (rAAV) vector to the CNS of mice, leading to a widespread periventricular distribution of transduction.Methods In the present study, we delivered rAAV2 vector expressing human NaGlu into the CNS of MPS IIIB mice by an i.c. injection approach, to test its therapeutic efficacy and feasibility for treating the neurological manifestation of the disease.Results We demonstrated significant functional neurological benefits of a single i.c. vector infusion in adult MPS IIIB mice. The treatment slowed the disease progression by mediating widespread recombinant NaGlu expression in the CNS, resulting in the reduction of brain lysosomal storage pathology, significantly improved cognitive function and prolonged survival. However, persisting motor function deficits suggested that pathology in areas outside the CNS contributes to the MPS IIIB behavioral phenotype. The therapeutic benefit of i.c. rAAV2 delivery was dose-dependent and could be attribute solely to the CNS transduction because the procedure did not lead to detectable transduction in somatic tissues.Conclusions A single IC rAAV2 gene delivery is functionally beneficial for treating the CNS disease of MPS IIIB in mice. It is immediately clinically translatable, with the potential of improving the quality of life for patients with MPS IIIB. Copyright (C) 2010 John Wiley & Sons, Ltd.