PATHOPHYSIOLOGY AND NOVEL THERAPIES FOR BATTEN'S DISEASE

巴顿病的病理生理学和新疗法

• 批准号: 8475693
• 负责人: Mark S Sands
• 金额: $ 38.28万
• 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: 2002-04-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8475693
• 关键词: 5 year old; Adverse event; Affect; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Biochemical; Blindness; Bone Marrow Transplantation; Brain; Cells; Cessation of life; Characteristics; Child; Childhood; Clinical; Cognitive deficits; Data; Disease; Employee Strikes; Enzymes; Foundations; Functional disorder; Goals; Impaired cognition; Infantile neuronal ceroid lipofuscinosis; Inherited; Integral Membrane Protein; Light; Longevity; Lysosomal Storage Diseases; Mediating; Minor; Modeling; Molecular; Motor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Ceroid-Lipofuscinosis; Neurons; Oral; Outcome; Pathogenesis; Pharmaceutical Preparations; Progress Reports; Regimen; Research; Seizures; Spielmeyer-Vogt Disease; Stem cells; Systemic disease; Therapeutic; Tissues; Treatment Efficacy; Visual; antioxidant therapy; base; conditioning; disease characteristic; effective therapy; enzyme deficiency; enzyme replacement therapy; gene therapy; human disease; improved; infancy; neuronal cell body; novel; novel strategies; pre-clinical; premature; research study; small molecule; therapy development; thioesterase PPT1 gene product; tool; vector

DESCRIPTION (provided by applicant): Batten disease represents a group of inherited neurodegenerative diseases also referred to as the Neuronal Ceroid Lipofuscinoses (NCLs). There are at least 8 genetically distinct forms of NCL and collectively, they are the most common pediatric neurodegenerative disease. The defining characteristic of the NCLs is the progressive accumulation of autofluorescent material in cells of the CNS and other tissues. Clinically, this group of pediatric neurodegenerative diseases typically present first with visual deficits followed by cognitive decline, intractable seizures, and premature death. Infantile Neuronal Ceroid Lipofuscinosis (INCL, Infantile Batten disease) is the most rapidly progressing form of NCL and is caused by the deficiency of the soluble lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1). There is currently no effective therapy for INCL. In fact, pre-clinical experiments in the murine model of INCL using a variety of approaches such as gene therapy, small molecule drugs, and neuronal stem cells have resulted in minor biochemical and histological improvements with essentially no increase in life span. However, we recently showed that CNS-directed gene therapy using an AAV2/5 vector resulted in a 50% increase in life span (INCL ~8mo, AAV2/5-INCL ~12mo). Interestingly, when bone marrow transplantation (BMT) was combined with AAV2/5 the median life span increased to ~18.5mo with a sustained improvement in motor function. These results are truly striking in light of the fact that BMT alone resulted in no detectable PPT1 activity in the brain and provided no biochemical or histological improvements. It is becoming clear that a combination approach targeting different aspects of disease can dramatically improve the clinical outcomes of INCL. We have identified several disease characteristics of INCL that can be targeted simultaneously. This combination approach could represent the foundation of therapies that will provide meaningful clinical benefit for affected children. The goals of this proposal are to: 1) better understand the interaction of BMT and CNS-directed gene therapy in the treatment of INCL and, 2) determine the efficacy of combining disparate therapeutic approaches that target different aspects of INCL. We will accomplish these goals with the following Specific Aims: 1) We will determine the mechanism of synergy between BMT and CNS-directed gene therapy. 2) We will determine the efficacy of therapeutic combinations that target different aspects of INCL.

描述（由申请人提供）：淡淡的疾病代表一组遗传性神经退行性疾病，也称为神经元ceroid脂肪糖蛋白酶（NCLS）。至少有8种遗传学形式的NCL形式，共同是最常见的小儿神经退行性疾病。 NCLS的定义特征是CNS和其他组织细胞中自动荧光材料的逐渐积累。在临床上，这组小儿神经退行性疾病通常首先出现视觉缺陷，随后是认知能力下降，顽固性癫痫发作和过早死亡。婴儿神经元的脂肪促脂肪促脂肪促脂蛋白（含，婴儿the病）是NCL的最快进展形式，是由可溶性溶酶体质酰基棕榈酰蛋白硫代酯蛋白硫代酶-1（PPT1）的缺乏引起的。目前没有有效的疗法。实际上，使用多种方法（例如基因治疗，小分子药物和神经元干细胞）的鼠模型中的临床前实验导致了较小的生化和组织学改善，其寿命基本上没有增加。但是，我们最近表明，使用AAV2/5载体的CNS定向基因治疗导致寿命增加50％（包括〜8MO，AAV2/5-INCL〜12MO）。有趣的是，当将骨髓移植（BMT）与AAV2/5结合使用时，中位寿命增加到〜18.5mO，运动功能持续改善。鉴于单独BMT的事实，这些结果确实令人惊讶 导致没有可检测到的PPT1活性，并且没有提供生化或组织学改进。越来越明显的是，针对疾病不同方面的组合方法可以极大地改善含有的临床结果。我们已经确定了可以同时靶向的几种疾病特征。这种组合方法可以代表疗法的基础，该疗法将为受影响的儿童提供有意义的临床益处。该提案的目标是：1）更好地了解BMT和CNS指导基因治疗在含含的治疗中的相互作用和，2）确定将靶向含有不同方面的不同治疗方法相结合的功效。我们将以以下特定目的来实现这些目标：1）我们将确定BMT和CNS指导基因治疗之间协同作用的机理。 2）我们将确定针对含有不同方面的治疗组合的功效。