Pathophysiology and Novel Therapies for Batten's Disease

巴滕氏病的病理生理学和新疗法

• 批准号: 8091219
• 负责人: Mark S Sands
• 金额: $ 31.5万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8091219
• 关键词: 6 year old; Acids; Affect; Astrocytes; Autopsy; Behavior; Biochemical; Bone Marrow Transplantation; Brain; Cessation of life; Child; Childhood; Clinical; Cognitive deficits; Data; Development; Disease; Disease Progression; Exhibits; Frequencies; Functional disorder; Funding; Goals; Grant; Hydrolase; Individual; Infantile neuronal ceroid lipofuscinosis; Inherited; Live Birth; Lysosomal Storage Diseases; Measures; Mediating; Metabolic Diseases; Metachromatic Leukodystrophy; Modeling; Mucopolysaccharidosis VII; Mus; Nerve Degeneration; Neuraxis; Neuroglia; Neuronal Ceroid-Lipofuscinosis; Neurons; Phenotype; Physiological; Proteins; Research; Research Personnel; Seizures; Silicon Dioxide; Spielmeyer-Vogt Disease; Testing; Therapeutic; Visual; aged; congenic; disease natural history; effective therapy; enzyme replacement therapy; gene therapy; innovation; neurodegenerative phenotype; novel; novel therapeutic intervention; premature; small molecule; thioesterase PPT1 gene product; tool

DESCRIPTION (provided by applicant): Infantile neuronal ceroid lipofuscinosis (INCL) is a neurodegenerative lysosomal storage disease (LSD) caused by a deficiency in palmitoyl protein thioesterase-1 (PPT1) activity. This leads to the accumulation of autofluorescent material in enurons and glia of the brain. The first clinical sign of INCL is visual dysfunction followed by cognitive deficits, seizures and premature death. The PPT1-deficient mouse is a powerful tool to uncover the mechanisms of disease and test novel therapeutic approaches for INCL. During the initial funding period of this grant we made significant progress in understanding the underlying pathophysiology of INCL. However, there is still much to be understood regarding the underlying mechanisms of disease. Currently, there is no effective therapy for INCL and traditional approaches such as enzyme replacement therapy (ERT) and bone marrow transplantation (BMT) are only minimally effective for rapidly progressing LSDs with profound CNS components. Successful treatment of INCL will require the development of new and innovative approaches. We showed that significant reductions in the accumulation of autofluorescent storage material, and improvments in behavior and seizure phenotype can be achieved following AAV- mediated, CNS-directed gene therapy. Although statistically significant, these improvments were modest. This is in contrast to other models of LSD that respond more completely to CNS-directed gene therapy. These data highlight the differences between LSDs and the need to develop more effective therapies for eac of these disorders, The goals of this research are to more completely understand the mechanisms of disease and devise more effective therapies approaches for INCL. We will accoumplish these goals with the following Specific Aims: 1) We will complete the biochemical, histological and physiological characterization of the PPT1-deficient mouse on the congenic C57BI/6 background. 2) We will determine the individual contributions of astrocytes and neurons to the progression of INCL i the congenic murine model of INCL. 3) We will determine the efficacy of CNS-directed AAV2/5-mediated gene therapy alone, and in combination with bone marrow transplantation or small molecule substrate depletion in the congenic PPT1-deficient mouse.

描述（申请人提供）：婴儿神经元蜡样质脂褐质沉着症（INCL）是一种由棕榈酰蛋白硫酯酶-1（PPT1）活性缺陷引起的神经退行性溶酶体贮积病（LSD）。这导致自发荧光物质在大脑的 enurons 和神经胶质细胞中积累。 INCL 的第一个临床症状是视觉功能障碍，随后是认知缺陷、癫痫发作和过早死亡。 PPT1 缺陷小鼠是揭示疾病机制和测试 INCL 新颖治疗方法的有力工具。在这笔赠款的初始资助期间，我们在理解 INCL 的潜在病理生理学方面取得了重大进展。然而，关于疾病的潜在机制仍有很多有待了解。目前，对于 INCL 尚无有效的治疗方法，酶替代疗法 (ERT) 和骨髓移植 (BMT) 等传统方法对于具有严重中枢神经系统成分的快速进展的 LSD 效果甚微。 INCL 的成功治疗需要开发新的创新方法。我们表明，通过 AAV 介导、CNS 导向的基因治疗，可以显着减少自发荧光存储材料的积累，并改善行为和癫痫表型。尽管在统计上具有显着性，但这些改进是有限的。这与其他 LSD 模型形成鲜明对比，其他 LSD 模型对中枢神经系统导向的基因治疗反应更完全。这些数据凸显了 LSD 之间的差异，以及为这些疾病开发更有效疗法的必要性。这项研究的目标是更全面地了解疾病机制，并为 INCL 设计更有效的治疗方法。我们将通过以下具体目标来实现这些目标：1）我们将在同源 C57BI/6 背景下完成 PPT1 缺陷小鼠的生化、组织学和生理学表征。 2）我们将在 INCL 的同类小鼠模型中确定星形胶质细胞和神经元对 INCL 进展的个体贡献。 3) 我们将确定中枢神经系统定向的 AAV2/5 介导的基因治疗单独的功效，以及与骨髓移植或小分子底物耗竭相结合的同源 PPT1 缺陷小鼠的功效。