AAV Mediated Gene Therapy to the CNS for MPS I

AAV 介导的 MPS I 中枢神经系统基因治疗

• 批准号: 8700139
• 负责人: Chester B. Whitley
• 金额: $ 27.89万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700139
• 关键词: Adult; Affect; Aftercare; Age; Allogenic; Animal Model; Animals; Applications Grants; Area; Blood - brain barrier anatomy; Brain; Breathing; Canis familiaris; Capsid; Cardiopulmonary; Cell Culture Techniques; Cells; Cessation of life; Clinical Protocols; Cornea; Data; Dermatan Sulfate; Deterioration; Development; Disease; Effectiveness; Enzymes; Exhibits; Face; Gene Delivery; Gene Expression; Gene Transfer; Genes; Glycosaminoglycans; Green Fluorescent Proteins; Heart; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Heparitin Sulfate; Hepatosplenomegaly; Human; Impaired cognition; Impairment; Individual; Infusion procedures; Inherited; Instruction; L-Iduronidase; Mediating; Memory; Mental Retardation; Metabolic Diseases; Morbidity - disease rate; Mucopolysaccharidosis I; Mus; Neonatal; Nerve Degeneration; Neuraxis; Neurocognitive; Neurocognitive Deficit; Neurologic; Neurologic Manifestations; Neurons; Newborn Infant; Obstruction; Patients; Pilot Projects; Population; Positioning Attribute; Prevention; Procedures; Proteins; Regimen; Relative (related person); Route; Serotyping; Slice; Stem cell transplant; Syndrome; Testing; Time; Tissue Sample; Tissues; Treatment Effectiveness; adeno-associated viral vector; brain tissue; cerebral atrophy; compare effectiveness; enzyme replacement therapy; gene therapy; improved; morris water maze; mortality; neurocognitive test; prevent; relating to nervous system; skeletal abnormality; skeletal dysplasia; standard of care; vector; way finding; white matter

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive storage disease caused by absence of a-L- iduronidase (IDUA), resulting in systemic accumulation of glycosaminoglycan 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 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 ofthe brain 10 months after intracerebroventricular infusion of neonatal (4-6 day old) MPS I mice with an AAV8 vector transducing the human IDUA gene, completely preventing 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. However, there are several challenges that must be faced in the development of this approach for treatment of MPS I in humans: (1) We will evaluate the effectiveness of intrathecal, intranasal, and endovascular (with blood brain barrier disruption) routes of AAV vector infusion to identify a less invasive means of administration for human IDUA gene delivery and expression in the CNS. (ii) We will evaluate /VW-mediated IDUA gene transfer to the CNS in iduronidase-deficient dogs as a large animal model of MPS I. We will also pilot a new neurocognitive testing regimen in these animals to evaluate the effectiveness of vector treatment in preventing neurologic decline in the animals, (iii) We will compare the effectiveness of several different AAV serotypes for gene transfer efficiency in human neuronal primary cultures and brain tissue slices. Results from these studies will directly impact the development of AAV-mediated IDUA gene transfer as an approach for improved therapy of MPS I, with implications for application of AAV mediated gene transfer for related neurologic diseases.

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive storage disease caused by absence of a-L- iduronidase (IDUA), resulting in systemic accumulation of glycosaminoglycan storage materials, hepatosplenomegaly, skeletal dysplasias, cardiopulmonary obstruction, progressive neurologic impairment and death by age 15. MPS I is currently treated by酶替代疗法（ERT）和同种异体造血干细胞移植（HSCT），但是这些治疗的神经系统效果受到提供给大脑提供的IDUA酶的限制。在这项提议中，我们提供了初步数据，表明在大脑的所有区域中，在脑室内注入新生儿（4-6天大）MPS I（4-6天大）MPS I小鼠的脑室内注入后，大脑的所有区域中的IDUA酶表达（2至40倍）（正常）（正常）（正常）。空间导航和内存的迷宫测试。这些前所未有的结果表明，AAV介导的IDUA基因直接转移到CNS具有克服ERT和HSCT治疗中ERT和HSCT的当前局限性的潜力AAV载体输注以确定人类IDUA基因递送和中枢神经系统表达的侵入性较低的给药手段。 （ii）我们将评估 /VW介导的IDUA基因转移到IDuronidase缺陷型狗作为MPS I的大动物模型。我们还将在这些动物中试验一种新的神经认知测试方案，以评估媒介治疗的有效性，以预防几个动物的神经学效率（ii ii），我们将在载体治疗中的有效性，（iii ii），我们将效率不同，我们将效率（III II III）效应，我们将效应效率。原发性培养和脑组织切片。这些研究的结果将直接影响AAV介导的IDUA基因转移的发展，作为改善MPS I治疗的方法，这对应用AAV介导的基因转移用于相关神经系统疾病的影响有影响。