Early intervention to restore OL and myelin development in leukodystrophy model

早期干预以恢复脑白质营养不良模型中的 OL 和髓磷脂发育

• 批准号: 7568188
• 负责人: JEAN DE VELLIS
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7568188
• 关键词: ARHGEF5 gene; Acetates; Affect; Age; Animal Model; Apoptotic; Aspartic Acid; Aspartoacylase; Axon; Birth; Brain; Canavan Disease; Cell Death; Cell Maturation; Cell physiology; Cells; Cessation of life; Child; Childhood; Corpus Callosum; Development; Disease; Early treatment; Embryo; Event; Exhibits; Failure; Functional disorder; Future; Gene Expression; Gene Mutation; Generations; Genes; Human; Impairment; Knock-out; Knockout Mice; Mediating; Mental Retardation; Metabolic; Modeling; Morphology; Mouse Strains; Mus; Mutation; Myelin; Myelin Basic Proteins; Myelin Proteins; Myelin Sheath; N-acetylaspartate; Neurodegenerative Disorders; Oligodendroglia; Population; Prevention; Prosencephalon; Proteins; Research; Research Personnel; Rodent Model; Role; Staging; Subfamily lentivirinae; Symptoms; Testing; Therapeutic Intervention; Transcript; Viral; Work; abstracting; brain morphology; cohort; early childhood; enzyme activity; gene therapy; in utero; lateral ventricle; leukodystrophy; motor deficit; mouse model; myelination; oligodendrocyte lineage; progenitor; pup; ranpirnase; repaired; restoration; success; therapy development; white matter

DESCRIPTION (provided by applicant): Abstract Project Summary: The objective of our research is to elucidate the role of myelin gene mutation on oligodendrocyte (OL) cell maturation and ensheathment of axons, failure of which results in hypomyelination that leads to leukodystrophy. Canavan disease (CD) is an example of such leukodystrophy which is caused by a metabolic mutation in aspartoacylase (ASPA) gene. Now recognized as a marker for OL cells, ASPA metabolizes N-acetyl aspartate (NAA) to release acetate and aspartic acid. The pathophysiology of this childhood disorder includes a spongy white matter morphology, mental retardation, megalencephaly, NAA aciduria, motor deficit, and early death. Because young children affected by Canavan disease display hypomyelination, the question arises whether this early event is indicative of OL dysfunction. An ASPA knockout (KO) mouse strain lacks expression of ASPA protein and enzyme activity, and closely resembles symptoms of human CD. Our preliminary work has shown that the ASPA knockout OLs exhibit lack of mature myelin basic proteins and lack of immunostaining of myelin proteins in cell processes in the CNS, even though presence of transcripts for myelin genes were identified. This suggests that expression of ASPA is critical during early stages of development for the maturation of OLs. In addition, a massive apoptotic cell death occurs in the CNS of ASPA knockout mice. Gene therapy was approved to another group of researchers, who administered an adenoviral-associated viral (AAV)-mediated ASPA gene therapy in a cohort of CD children, and in rodent models of CD after the peak period of myelination. No improvement in spongy white matter morphology was detected. During early development, OL progenitors arise embryonically, and yet another OL lineage is generated post- birth to populate the forebrain. Therefore, we propose to target these two early populations of OLs for delivery of ASPA gene to induce OL maturation and function in the KO brain. The findings will help understand the role of ASPA in prevention of leukodystrophy and will be useful for future development of therapies. Abstract Narrative: Objective of this proposal is to restore aspartoacylase activity during the embryonic and post-natal period of mouse model of Canavan Disease (CD). We will demonstrate that activity of this gene is critically necessary for the normal development of the myelin forming cells and the ensheathment of axons that is essential for normal CNS function. If successful, information from this study could be used to develop appropriate therapeutic interventions for the treatment of children affected by CD, the most devastating disease that causes mental retardation and death.

描述（由申请人提供）：摘要项目摘要：我们的研究目的是阐明髓鞘基因突变对少突胶质细胞（OL）细胞成熟和轴突鞘化的作用，其失败会导致髓鞘形成不足，从而导致脑白质营养不良。Canavan病（CD）是这种脑白质营养不良的一个例子，其由乙酰氨基酰化酶（ASPA）基因中的代谢突变引起。现在被认为是OL细胞的标志物，ASPA代谢N-乙酰天冬氨酸（NAA）释放乙酸和天冬氨酸。这种儿童期疾病的病理生理学包括海绵状白色物质形态、智力迟钝、巨脑畸形、NAA酸尿症、运动缺陷和早死。由于受卡纳万病影响的幼儿显示髓鞘形成不足，问题是这种早期事件是否表明OL功能障碍。ASPA敲除（KO）小鼠品系缺乏ASPA蛋白表达和酶活性，并且与人CD的症状非常相似。我们的初步工作已经表明，ASPA敲除的OL表现出缺乏成熟的髓鞘碱性蛋白和缺乏髓鞘蛋白的免疫染色的细胞过程中的CNS，即使髓鞘基因的转录本的存在被确定。这表明ASPA的表达在发育的早期阶段对于OL的成熟至关重要。此外，ASPA敲除小鼠的CNS中发生大量凋亡性细胞死亡。基因治疗被批准给另一组研究人员，他们在一组CD儿童和髓鞘形成高峰期后的CD啮齿动物模型中给予腺病毒相关病毒（AAV）介导的ASPA基因治疗。未检测到海绵状白色物质形态的改善。在早期发育过程中，OL祖细胞在胚胎中产生，而另一个OL谱系在出生后产生以填充前脑。因此，我们建议靶向这两个早期OL群体，用于递送ASPA基因以诱导KO脑中的OL成熟和功能。这些发现将有助于理解ASPA在预防脑白质营养不良中的作用，并将有助于未来治疗的发展。 摘要叙述：本提案的目的是在卡纳万病（CD）小鼠模型的胚胎和出生后期间恢复β-酰化酶活性。我们将证明该基因的活性对于髓鞘形成细胞的正常发育和轴突的鞘化是至关重要的，而轴突的鞘化是正常CNS功能所必需的。如果成功的话，这项研究的信息可以用来制定适当的治疗干预措施，用于治疗受CD影响的儿童，CD是导致智力迟钝和死亡的最具破坏性的疾病。