Pathophysiology and Novel Therapies for Batten's Disease

描述（由申请人提供）：婴儿神经性蜡样脂褐质病（INCL）是一种神经退行性溶酶体贮积病（LSD），由棕榈酰蛋白硫酯酶-1 （PPT1）活性缺乏引起。这导致自身荧光物质在大脑的神经元和神经胶质中积累。INCL的第一个临床症状是视觉功能障碍，其次是认知缺陷、癫痫发作和过早死亡。ppt1缺陷小鼠是揭示疾病机制和测试新的INCL治疗方法的有力工具。在本基金的初始资助期间，我们在了解INCL的潜在病理生理方面取得了重大进展。然而，关于疾病的潜在机制仍有许多有待了解。目前，INCL没有有效的治疗方法，传统的方法，如酶替代疗法（ERT）和骨髓移植（BMT），仅对具有深刻中枢神经系统成分的快速进展的lsd有效。成功治疗INCL将需要发展新的和创新的方法。我们发现，在AAV介导的中枢神经系统导向的基因治疗后，可显著减少自身荧光储存物质的积累，改善行为和癫痫表型。尽管这些改善在统计学上意义重大，但并不明显。这与其他对中枢神经系统导向的基因疗法反应更完全的LSD模型形成对比。这些数据强调了lsd之间的差异，以及开发更有效的治疗方法的必要性，本研究的目标是更全面地了解疾病的机制，并设计出更有效的治疗方法，我们将实现这些目标：1)我们将完成基因C57BI/6背景下ppt1缺陷小鼠的生化，组织学和生理学特征。2)我们将在同源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)我们将在同源ppt1缺陷小鼠中确定cns定向的aav2 /5介导的基因治疗单独，以及联合骨髓移植或小分子底物去除的疗效。

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.