Pathophysiology and Novel Therapies for Batten's Disease

描述（由申请方提供）：婴儿神经元蜡样质脂褐质沉积症（INCL）是一种由棕榈酰蛋白硫酯酶-1（PPT1）活性缺乏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脑的enuron和神经胶质中积累。INCL的第一个临床体征是视觉功能障碍，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新治疗方法的有力工具。在最初的资助期间，我们在了解INCL的基础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问题需要了解。目前，对于INCL没有有效的治疗方法，并且传统方法如酶替代疗法（ERT）和骨髓移植（BMT）对于具有深刻CNS组分的快速进展的LSD仅具有最低限度的有效性。INCL的成功治疗将需要开发新的和创新的方法。我们表明，在AAV介导的CNS指导的基因治疗后，可以实现自发荧光储存物质积累的显著减少以及行为和癫痫发作表型的改善。虽然在统计学上有显著意义，但这些改进是适度的。这与LSD的其他模型形成对比，这些模型对CNS指导的基因治疗有更完全的反应。这些数据突出了LSD之间的差异，以及为这些疾病开发更有效治疗方法的必要性。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。本研究的具体目标如下：1）以C57 BI/6为背景，完成PPT 1缺陷小鼠的生化、组织学和生理学特性研究。2)我们将确定星形胶质细胞和神经元对INCL进展的贡献。3)我们将确定CNS导向的AAV2/5介导的基因治疗单独以及与骨髓移植或小分子底物消耗相结合在同源PPT 1缺陷小鼠中的功效。

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.