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: 6685204
• 负责人: Mark S Sands
• 金额: $ 27.06万
• 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 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6685204
• 关键词: Pathophysiology; Novel; Therapies; Batten; Disease

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.

描述(申请人提供)：神经性干酪样脂褐质增多症(NCL，巴顿病)是一种遗传性神经退行性疾病，主要影响儿童。NCLS的一个特征是在包括大脑神经元在内的多种细胞类型的溶酶体中积累自体荧光物质。患有NCL的儿童患有失明、癫痫、运动和智力恶化以及过早死亡。NCL的最早形式是婴儿神经元性蜡样脂褐素沉着症(InCL)，由可溶性溶酶体酶棕榈酰蛋白硫酯酶-1(PPT1)缺乏引起，因此被归类为溶酶体储存性疾病。目前，对INCL尚无有效的治疗方法。我们最近获得了一种新的PPT1缺乏症小鼠模型。虽然目前对这种模型的疾病进展知之甚少，但它完全缺乏PPT1活性，自发荧光物质在大脑的神经元中积聚。仅这两个特征就使其成为研究疾病进展和开发新的治疗方法的有价值的小动物模型。最近在另一种溶酶体储存性疾病的小鼠模型中发现，直接脑内注射Agene转移载体可以减少溶酶体在大脑中的蓄积，改善认知功能。由于许多溶酶体酶之间的生化相似性，我们认为使用重组病毒载体的基因治疗方法也可能被证明对INCL有效。本研究的长期目标是确定PPT1缺陷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陷和保护这些功能方面的效果。我们将通过以下具体目标来实现这些目标：1.构建和鉴定编码人棕榈酰基蛋白硫酯酶-1(PPT1)的重组AAV和慢病毒Gone转移载体。2.我们将确定PPT1缺陷小鼠临床疾病的进展和程度，特别是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PPT1缺陷小鼠的INCL的疗效。