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

针对 IIIA 型 MPS 的自我互补 rAAV9 全身基因递送治疗

基本信息

批准号：
8554388
负责人：
Douglas M McCarty
金额：
$ 17.55万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8554388
关键词：
Address Affect Age Aggressive behavior Animal Testing Animals Area Birth Blood - brain barrier anatomy Blood Circulation Bone Marrow Transplantation Brain Bypass Cell Line Cells Central Nervous System Diseases Child Clinical Clinical Trials Code Cognitive DNA Data Dementia Dependovirus Deterioration Development Diagnosis Disease Employee Strikes Enzymes Episome Family Gene Delivery Gene Expression General Population Genes Glycosaminoglycans Goals Hand Healthcare Systems Hereditary Disease Histocompatibility Testing Human Immunity Incidence Infant Inherited Injection of therapeutic agent Lead Lysosomal Storage Diseases Lysosomes Mission Mitotic Mucopolysaccharidoses Mucopolysaccharidosis III Mus Nerve Degeneration Neuraxis Neurologic Manifestations Neurons Neurotropism Operative Surgical Procedures Outcome Palliative Care Parents Pathology Patients Peripheral Plant Roots Preparation Probability Problem behavior Procedures Process Production Property Public Health Quality of life Recombinant adeno-associated virus (rAAV)Recombinants Research Research Project Grants Serotyping Single-Stranded DNA Sleep disturbances Staging Supportive care System Technology Teenagers Testing Therapeutic Therapeutic Effect Therapeutic Studies Therapeutic procedure Time Tissues Toxicology Transgenes Translations Treatment Efficacy Viral Vector Virus Work adeno-associated viral vector alpha-n-acetylglucosaminidase base cellular transduction cost design disability ds-DNA early childhood effective therapy emerging adult gene delivery system gene therapy improved intravenous injection mouse model nervous system disorder neuropathology nonhuman primate novel optimism patient population promoter research clinical testing scale up therapy development transduction efficiency transgene expression treatment strategy vector viral gene delivery

项目摘要

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.

描述（由申请人提供）：目前还没有针对与溶酶体贮积病、粘多糖贮积症 IIIA (MPS IIIA) (Sanfilippo A) 相关的神经变性的破坏性影响的治疗方法。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，以及认知能力下降，进而发展为痴呆。患者通常能存活到成年早期，并且需要强烈的支持性护理。基因治疗可以有效治疗疾病的根本原因——编码N-磺基葡萄糖胺磺基水解酶（SGSH）的基因缺陷，并在细胞水平上纠正病理，从而清除溶酶体中积累的糖胺聚糖（GAG）。由于 MPS IIIA 的神经病理学是全球性的，影响大脑的所有区域，因此将基因有效传递到中枢神经系统 (CNS) 是治疗这种疾病以及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基因治疗程序来治疗 MPS IIIA 疾病。最近观察到，与任何其他已知病毒载体不同，源自血清型 9 (AAV9) 的重组腺相关病毒 (rAAV) 载体在小鼠静脉注射后能够从血流中穿过血脑屏障 (BBB)和其他动物。这一特征为治疗 MPS IIIA 提供了一种均质 CNS 基因递送的新方法。由于人类 SGSH 编码区很小，因此可以通过使用 rAAV 载体的衍生物、自互补 AAV (scAAV) 来最大化 CNS 内载体转导细胞的数量和分布。 scAAV 载体绕过了将母体病毒的单链 DNA 转化为双链 DNA 进行基因表达的要求，并且在许多组织中将转导效率提高了几个数量级。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 hSGSH 表达和治疗效果，以及 2) 测试疾病后期的治疗效果，以反映治疗 MPS IIIA 患者的临床现实人口。该研究策略的基本原理是，它将 AAV9 的新颖基因传递特性与 scAAV 和紧凑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躯体疾病的可能性。拟议的研究意义重大，因为它解决了有效基因疗法治疗一系列神经系统疾病的最大障碍。该项目的成功完成预计将对 MPS IIIA 患者群体产生直接影响，并提供可行的治疗程序以推进临床测试过程。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Functional correction of neurological and somatic disorders at later stages of disease in MPS IIIA mice by systemic scAAV9-hSGSH gene delivery.

通过全身性 scAAV9-hSGSH 基因递送对 MPS IIIA 小鼠疾病后期的神经和躯体疾病进行功能纠正。

DOI：
发表时间：
2016
期刊：
影响因子：
0
作者：
Fu, Haiyan;Cataldi, Marcela P;Ware, Tierra A;Zaraspe, Kimberly;Meadows, Aaron S;Murrey, Darren A;McCarty, Douglas M
通讯作者：
McCarty, Douglas M