Self-complementary rAAV9 Systemic Gene Delivery Treatment for MPS Type IIIA

描述（由申请方提供）：目前尚无治疗与溶酶体贮积病粘多糖沉积症IIIA（MPS IIIA）（Sanfilippo A）相关的神经变性的破坏性影响的方法。遗传这种单基因疾病的儿童通常在出生时没有症状，但在1-4岁时开始出现严重的行为问题，包括攻击性和睡眠障碍，以及发展为痴呆的认知退化。患者通常能存活到成年早期，需要密集的支持性护理。基因治疗可以有效地治疗疾病的根本原因，即编码N-磺基葡糖胺磺基水解酶（SGSH）的基因缺陷，并在细胞水平上纠正病理，导致溶酶体中积累的糖胺聚糖（GAG）的清除。由于MPS IIIA的神经病理学是全球性的，影响大脑的所有区域，因此向中枢神经系统（CNS）有效的基因递送是治疗这种疾病和许多其他溶酶体贮积病的最大障碍。该项目的近期目标是开发一种治疗MPS IIIA疾病的基因治疗程序。最近已经观察到，与任何其他已知的病毒载体不同，源自血清型9（AAV 9）的重组腺相关病毒（rAAV）载体在小鼠和其他动物中静脉内注射后能够从血流穿过血脑屏障（BBB）。该特征提供了一种用于治疗MPS IIIA的均质CNS基因递送的新方法。因为人SGSH编码区小，所以通过使用rAAV载体的衍生物，自身互补AAV（scAAV），可以使CNS内载体转导的细胞的数量和分布最大化。scAAV载体绕过了将亲本病毒的单链DNA转化为用于基因表达的双链DNA的要求，并且在许多组织中使转导效率成倍增加。该提案的具体目的是1）比较scAAV和单链AAV载体在MPSIIIA小鼠中的hGSH表达和治疗效果，和2）测试疾病后期的治疗功效以反映治疗MPS IIIA患者群体的临床现实。该研究策略的基本原理是，它将AAV 9的新基因递送特性与scAAV和紧凑型启动子的高效率相结合，以最大限度地提高成功治疗CNS病理以及与该疾病相关的相对较轻的体细胞疾病的可能性。这项拟议中的研究意义重大，因为它解决了对一系列神经系统疾病进行有效基因治疗的最大障碍。该项目的成功完成预计将对MPS IIIA患者人群产生直接影响，并将开展工作治疗程序以推进临床试验过程。

DESCRIPTION (provided by applicant): There is currently no treatment for the devastating impacts of neurodegeneration associated with the lysosomal storage disease, mucopolysaccharidosis IIIA (MPS IIIA) (Sanfilippo A). Children inheriting this monogenetic disorder are typically asymptomatic at birth, but at age 1-4 begin to develop severe behavioral problems including aggression and sleep disturbances, and cognitive deterioration that progresses to dementia. Patients usually survive to early adulthood and require intense supportive care. Gene therapy can effectively treat the root cause of the disease, a deficiency in the gene encoding N-sulfoglucosamine sulfohydrolase (SGSH), and correct the pathology at the cellular level, leading to clearance of accumulated glycosaminoglycans (GAGs) in lysosomes. Because the neuropathology of MPS IIIA is global, affecting all areas of the brain, effective gene delivery to the central nervous system (CNS) is the greatest obstacle to treatment for this, and many other lysosomal storage diseases. The immediate goal of this project is to develop a gene therapy procedure to treat MPS IIIA disease. It has been observed recently that recombinant adeno-associated virus (rAAV) vectors derived from serotype 9 (AAV9), unlike any other known viral vector, are able to cross the blood-brain barrier (BBB) from the bloodstream after intravenous injection in mice and other animals. This feature provides a novel means of homogeneous CNS gene delivery for the treatment of MPS IIIA. Because the human SGSH coding region is small, the number and distribution of vector-transduced cells within the CNS can be maximized by using a derivative of rAAV vectors, self-complementary AAV (scAAV). scAAV vectors bypass the requirement for converting the single-stranded DNA of the parent virus into double-strand DNA for gene expression, and multiply transduction efficiency by orders of magnitude in many tissues. The specific aims of this proposal are to 1) Compare scAAV and single-strand AAV vectors for hSGSH expression and therapeutic effect in MPSIIIA mice and 2) Test therapeutic efficacy in later stages of the disease to reflect the clinical realities of treatng the MPS IIIA patient population. The rationale for the research strategy is that it combines the novel gene delivery properties of AAV9 with the high efficiency of scAAV and compact promoters to maximize the probability of successfully treating CNS pathology, as well as the relatively milder somatic disorders associated with this disease. The proposed research is significant because it addresses the greatest obstacles to effective gene therapy treatment for a range of neurological disorders. Successful completion of the project is expected to have an immediate impact on the MPS IIIA patient population, with a working therapeutic procedure in hand to advance to the clinical testing process.