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）：巴顿病是一组遗传性神经退行性疾病，也被称为神经性Ceroid lipofuscinosis （NCLs）。NCL至少有8种遗传上不同的形式，它们是最常见的儿科神经退行性疾病。nclc的典型特征是自体荧光物质在中枢神经系统和其他组织细胞中逐渐积累。临床上，这组儿童神经退行性疾病通常首先表现为视力缺陷，随后是认知能力下降，难治性癫痫发作和过早死亡。婴儿神经性Ceroid Lipofuscinosis （INCL, infant Batten disease）是NCL进展最快的一种形式，由可溶性溶酶体酶棕榈酰蛋白硫酯酶-1 （PPT1）缺乏引起。目前还没有针对INCL的有效治疗方法。事实上，在INCL小鼠模型的临床前实验中，使用了多种方法，如基因治疗、小分子药物和神经干细胞，导致了轻微的生化和组织学改善，但基本上没有延长寿命。然而，我们最近发现，使用AAV2/5载体的cns定向基因治疗可使寿命延长50% （INCL ~8mo, AAV2/5-INCL ~12mo）。有趣的是，当骨髓移植（BMT）联合AAV2/5时，中位寿命增加到~18.5个月，运动功能持续改善。考虑到BMT本身的事实，这些结果确实令人震惊