AAV Mediated Gene Transfer to the CNS for MPS I

AAV 介导 MPS I 基因转移至 CNS

• 批准号: 8250741
• 负责人: Karen Kozarsky
• 金额: $ 21.1万
• 依托单位: REGENX BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-21 至 2014-09-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8250741
• 关键词: Address; Adverse event; Affect; Aftercare; Age; Allogenic; Animals; Applications Grants; Area; Blood - brain barrier anatomy; Brain; Breathing; Capsid; Cardiopulmonary; Cell Culture Techniques; Cells; Cessation of life; Clinical Protocols; Cornea; Data; Dependovirus; Dermatan Sulfate; Deterioration; Development; Disease; Effectiveness; Enzymes; Exhibits; Face; Family; Gene Delivery; Gene Expression; Gene Transfer; Genes; Genome; Glycosaminoglycans; Green Fluorescent Proteins; Heart; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Heparitin Sulfate; Hepatosplenomegaly; Human; Immune response; Impaired cognition; Impairment; Individual; Infusion procedures; Inherited; L-Iduronidase; Lysosomal Storage Diseases; Mediating; Memory; Mental Retardation; Metabolic; Minnesota; Morbidity - disease rate; Mucopolysaccharidosis I; Mucopolysaccharidosis I H; Mus; Neonatal; Nerve Degeneration; Neuraxis; Neurocognitive; Neurocognitive Deficit; Neurologic; Neurologic Manifestations; Neurons; Obstruction; Patients; Phase; Population; Prevention; Procedures; Proteins; Recombinant adeno-associated virus (rAAV); Relative (related person); Research; Route; Safety; Serotyping; Slice; Small Business Technology Transfer Research; Stem cell transplant; Technology; Testing; Time; Tissue Sample; Tissues; Treatment Effectiveness; Universities; adeno-associated viral vector; base; brain tissue; cellular transduction; cerebral atrophy; compare effectiveness; enzyme replacement therapy; experience; human disease; improved; in vivo; morris water maze; mortality; novel; pre-clinical; prevent; relating to nervous system; skeletal abnormality; skeletal dysplasia; standard of care; vector; way finding; white matter

DESCRIPTION (provided by applicant): Mucopolysaccharidosis type I (MPS I) is an autosomal recessive storage disease caused by the absence of a-L-iduronidase (IDUA), resulting in systemic accumulation of glycosaminoglycan (GAG) storage materials, hepatosplenomegaly, skeletal dysplasias, cardiopulmonary obstruction, progressive neurologic impairment and death by age 15. MPS I is currently treated by enzyme replacement therapy (ERT) and by allogeneic hematopoietic stem cell transplantation (HSCT), but the neurologic effectiveness of these treatments is limited by the amount of IDUA enzyme provided to the brain. In this proposal, we present preliminary data demonstrating extraordinarily high levels of IDUA enzyme expression (2- to 40-fold normal) in all areas of the brain 10 months after intracerebroventricular infusion of neonatal (4-6 day old) MPS I mice with an adeno-associated virus serotype 8 (AAV8) vector transducing the human IDUA gene. This high level of IDUA expression prevented accumulation of GAG storage material, and completely prevented emergence of neurocognitive deficits exhibited by untreated animals in a Morris water maze test of spatial navigation and memory. These unprecedented results demonstrate that AAV-mediated IDUA gene transfer directly to the CNS has the potential to overcome the current limitations of ERT and HSCT in the treatment of MPS I. ReGenX, LLC, is a leading company in the development of AAV vectors for treatment of human disease. In this Phase I STTR project, we propose to combine ReGenX AAV vector technology with the University of Minnesota's experience in the treatment of lysosomal storage diseases to address key challenges that must be faced in the development of AAV mediated IDUA gene transfer to the CNS for treatment of MPS I in humans: (i) Which AAV serotype is most effective in mediating gene transfer into human neuronal cells? To address this question, we will compare the effectiveness of AAV8, AAV9 and AAVrh.10 for gene transfer efficiency in human neuronal primary cultures and brain tissue slices. (ii) Is there a less invasive route of AAV vector administration that can be used to achieve effective and widespread IDUA expression in the brain, and that would be more acceptable to IDUA-deficient patients and their families? To address this question, we will evaluate the effectiveness of intrathecal, intranasal, and endovascular (with blood brain barrier disruption) routes of AAV vector administration for human IDUA gene delivery and expression in the CNS. Results from these studies will directly impact the development of AAV-mediated IDUA gene transfer to the CNS as an approach for improved therapy of MPS I, and will also have significance for the application of AAV mediated gene transfer to the CNS for related metabolic and neurologic diseases. PUBLIC HEALTH RELEVANCE: Lysosomal storage disorders are a rare group of inherited diseases in which patients suffer from skeletal abnormalities, heart and breathing problems, mental retardation and death. It is envisioned in this grant application that one way to treat these diseases would be to restore the missing gene in patients' central nervous system (in the brain) to prevent neurodegeneration.

描述（由申请方提供）：I型粘多糖样沉积症（MPS I）是一种由缺乏α-L-艾杜糖醛酸酶（IDUA）引起的常染色体隐性遗传病，导致糖胺聚糖（GAG）储存物质全身蓄积、肝脾肿大、骨骼发育不良、心肺阻塞、进行性神经功能损害和15岁以下死亡。MPS I目前通过酶替代疗法（ERT）和同种异体造血干细胞移植（HSCT）治疗，但这些治疗的神经学有效性受到提供给大脑的IDUA酶量的限制。在该提案中，我们提供了初步数据，证明在新生（4-6天）MPS I小鼠脑室内输注转导人IDUA基因的腺相关病毒血清型8（AAV 8）载体后10个月，大脑所有区域的IDUA酶表达水平异常高（2- 40倍正常）。这种高水平的IDUA表达阻止了GAG储存物质的积累，并完全阻止了在空间导航和记忆的Morris水迷宫测试中未处理动物表现出的神经认知缺陷的出现。这些前所未有的结果表明，AAV介导的IDUA基因直接转移至CNS有可能克服目前ERT和HSCT治疗MPS I的局限性。 ReGenX，LLC是开发用于治疗人类疾病的AAV载体的领先公司。在该I期STTR项目中，我们建议将联合收割机ReGenX AAV载体技术与明尼苏达大学在治疗溶酶体贮积病方面的经验相结合，以解决在开发AAV介导的IDUA基因转移至CNS以治疗人类MPS I中必须面临的关键挑战：（i）哪种AAV血清型在介导基因转移至人类神经元细胞中最有效？为了解决这个问题，我们将比较AAV 8、AAV 9和AAVrh.10在人神经元原代培养物和脑组织切片中的基因转移效率的有效性。(ii)是否有一种侵入性较小的AAV载体给药途径，可用于在脑中实现有效和广泛的IDUA表达，并且更容易被IDUA缺陷患者及其家属接受？为了解决这个问题，我们将评估鞘内、鼻内和血管内（具有血脑屏障破坏）途径的AAV载体施用对于人IDUA基因递送和CNS中表达的有效性。这些研究的结果将直接影响AAV介导的IDUA基因转移至CNS作为改善MPS I治疗的方法的发展，并且还将对AAV介导的基因转移至CNS用于相关代谢和神经系统疾病的应用具有重要意义。 公共卫生相关性：溶酶体贮积症是一组罕见的遗传性疾病，患者患有骨骼异常，心脏和呼吸问题，智力迟钝和死亡。在这项拨款申请中设想，治疗这些疾病的一种方法是恢复患者中枢神经系统（大脑）中缺失的基因，以防止神经变性。