Pathophysiology and Novel Therapies for Batten's Disease

描述（由申请方提供）：神经元蜡样脂褐质病（NCL，Batten病）是一种遗传性神经退行性疾病，主要影响儿童。NCL的一个标志是自发荧光物质在包括脑神经元在内的许多细胞类型的溶酶体中积累。患有NCL的儿童会失明、癫痫发作、运动和精神退化以及过早死亡。NCL的最早形式，婴儿神经元蜡样脂褐质沉积症（INCL），是由可溶性溶酶体酶棕榈酰蛋白硫酯酶-1（PPT 1）缺乏引起的，因此被归类为溶酶体贮积病。目前，对于INCL没有有效的治疗方法。我们最近获得了一个新开发的小鼠模型的PPT 1缺陷。 尽管对该模型中的疾病进展知之甚少，但它完全缺乏PPT 1活性，并且自发荧光物质在大脑神经元中积累。仅这两个特征就使其成为研究疾病进展和开发新治疗方法的有价值的小动物模型。最近在另一种溶酶体贮积病的小鼠模型中显示，直接颅内注射基因转移载体可以减少溶酶体贮积在脑中的积累并改善认知功能。由于许多溶酶体酶之间的生物化学相似性，我们认为使用重组病毒载体的基因治疗方法也可能证明对INCL有效。这项研究的长期目标是确定PPT 1缺乏对小鼠视觉和认知功能的影响，然后评估病毒介导的基因转移在纠正酶缺乏和保护这些功能方面的功效。我们将通过以下具体目标来实现这些目标：1.我们将在体外构建和鉴定编码人棕榈酰蛋白硫酯酶-1（PPT 1）的重组AAV和慢病毒基因转移载体。 2.我们将确定临床疾病的进展和程度，特别是PPT 1缺陷小鼠中的视网膜和认知功能障碍。3.我们将确定病毒介导的基因治疗方法对PPT 1缺陷小鼠INCL的疗效。

DESCRIPTION (provided by applicant): Neuronal Ceroid Lipofuscinoses (NCL, Batten Disease) are inherited neurodegenerative diseases primarily affecting children. One hallmark of the NCLs is that accumulation of autofluorescent material in the lysosomes of many cell types including neurons of the brain. Children with NCL suffer from blindness, seizures, motor and mental deterioration and premature death. The earliest form of NCL, Infantile Neuronal Ceroid Lipofuscinosis (INCL), is caused by a deficiency in the soluble lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1) and is, therefore, classified as a lysosomal storage disease. Currently, there is no effective treatment for INCL. We recently obtained a newly developed mouse model of PPT1 deficiency. Although very little is known yet about the disease progression in this model, it is completely deficient in PPT1 activity and autofluorescent material accumulates in neurons of the brain. These two characteristics alone make this a valuable small animal model to study the disease progression and develop novel therapeutic approaches. It was recently shown in a murine model of another lysosomal storage disease that direct intracranial injection of agene transfer vector could reduce the accumulation of lysosomal storage in the brain and improve cognitive function. Due to the biochemical similarities between many lysosomal enzymes, we believe that a gene therapy approach using recombinant viral vectors may also prove efficacious for INCL. The long-term goals of this research are to determine the effects of PPT1 deficiency on visual and cognitive functions in the mouse and then evaluate the efficacy of viral-mediated gene transfer in correcting the enzyme deficiency and preserving these functions. We will accomplish these goals with the following specific aims: 1. We wil create and characterize in vitro recombinant AAV and lentiviral gone transfer vectors encoding human palmitoyl protein thioesterase-1 (PPT1). 2. We will determine the progression and extent of clinical disease, especially the retinal and cognitive dysfunction in the PPTl-deficient mouse. 3. We will determine the efficacy of viral-mediated gene therapy approaches for INCL in the PPT1 deficient mouse.