Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
J Gene Med. 2010 Jul;12(7):624-33. doi: 10.1002/jgm.1480.
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.
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.
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.
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.
寻找有效的中枢神经系统（CNS）传递方法一直是治疗具有全球神经表现的疾病（如粘多糖贮积症 IIIB）的治疗开发所面临的主要挑战，该病是由溶酶体贮积症的常染色体隐性缺陷引起的α-N-乙酰氨基葡萄糖苷酶（NaGlu）。以前，我们开发了一种方法，即通过脑室内（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，导致广泛的室周分布转导。
在本研究中，我们通过脑室内注射方法将表达人类 NaGlu 的 rAAV2 载体递送至 MPS IIIB 小鼠的中枢神经系统，以测试其治疗疗效和治疗该疾病神经表现的可行性。
我们证明了单次脑室内载体输注对成年 MPS IIIB 小鼠具有显著的功能性神经益处。该治疗通过在中枢神经系统中介导广泛的重组 NaGlu 表达，从而减缓疾病进展，减少脑溶酶体贮积病理，显著改善认知功能并延长生存时间。然而，持续的运动功能缺陷表明中枢神经系统以外的区域的病理对 MPS IIIB 行为表型有贡献。脑室内 rAAV2 递送的治疗益处呈剂量依赖性，并且可以完全归因于中枢神经系统转导，因为该过程不会导致体细胞组织中可检测到的转导。
单次脑室内 rAAV2 基因传递对治疗 MPS IIIB 小鼠的中枢神经系统疾病具有功能益处。它具有立即的临床转化潜力，有可能改善 MPS IIIB 患者的生活质量。
