Pathophysiology and Novel Therapies for Batten's Disease

描述(申请人提供)：婴儿神经元型蜡样脂褐素沉积症(INCL)是一种由棕榈酰基蛋白硫酯酶-1(PPT1)活性不足引起的神经退行性溶酶体储存病(LSD)。这导致自体荧光物质在大脑的神经元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，随后是认知障碍、癫痫发作和过早死亡。PPT1基因缺陷小鼠是揭示INCL发病机制和测试新的治疗方法的有力工具。在这笔赠款的最初资助期间，我们在了解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许多需要了解。目前，INCL尚无有效的治疗方法，传统的治疗方法如酶替代疗法(ERT)和骨髓移植(BMT)对进展迅速、中枢神经系统成分丰富的LSD疗效甚微。INCL的成功治疗将需要开发新的和创新的方法。我们发现，AAV介导的CNS导向的基因治疗可以显著减少自发荧光存储物质的积累，并改善行为和癫痫表型。尽管在统计上意义重大，但这些改善并不严重。这与其他对中枢神经系统基因治疗有更完全反应的LSD模型形成了鲜明对比。这些数据突显了LSD之间的差异以及为这些疾病的EAC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，并为INCL设计更有效的治疗方法。我们将以以下具体目标来实现这些目标：1)在C57BI/6基因背景上完成PPT1基因缺陷小鼠的生化、组织学和生理特性研究。2)我们将确定星形胶质细胞和神经元在INCL同源小鼠模型进展中的单独作用。3)研究中枢神经系统介导的AAV2/5基因治疗对PPT1基因缺陷小鼠的疗效，以及联合骨髓移植或小分子底物去除治疗的效果。

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.