PATHOPHYSIOLOGY AND NOVEL THERAPIES FOR BATTEN'S DISEASE

描述（由申请人提供）：Batten病代表一组遗传性神经退行性疾病，也称为神经元蜡样脂褐质病（NCL）。至少有9种遗传上不同的NCL形式，它们是最常见的儿科神经退行性疾病。NCL的定义特征是CNS和其他组织细胞中自发荧光物质的进行性积累。在临床上，这组儿童神经退行性疾病通常首先表现为视觉缺陷，然后是认知能力下降、顽固性癫痫发作和过早死亡。婴儿神经元蜡样脂褐质沉积症（INCL，婴儿巴滕病）是进展最快的NCL形式，由可溶性溶酶体酶棕榈酰蛋白硫酯酶-1（PPT 1）缺乏引起。目前还没有有效的治疗INCL的方法。事实上，在INCL小鼠模型中使用各种方法（如基因治疗、小分子药物和神经元干细胞）进行的临床前实验已导致轻微的生化和组织学改善，寿命几乎没有延长。然而，我们最近显示使用AAV 2/5载体的CNS定向基因治疗导致寿命增加50%（INCL ~ 8 mo，AAV 2/5-INCL ~ 12 mo）。有趣的是，当骨髓移植（BMT）与AAV 2/5组合时，中位寿命增加至约18.5个月，运动功能持续改善。这些结果确实令人震惊，因为BMT本身 导致在脑中没有可检测到的PPT 1活性，并且没有提供生物化学、组织学或临床改善。越来越清楚的是，针对疾病不同方面的联合方法可以显著改善INCL的临床结局。我们已经确定了INCL的几个疾病特征，可以同时靶向。这种组合方法可以代表治疗的基础，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）更好地理解BMT和CNS定向基因治疗在INCL治疗中的相互作用，2）确定针对INCL不同方面的不同治疗方法的组合疗效。我们将通过以下具体目标实现这些目标：1）我们将更全面地描述INCL小鼠对AAV 2/5和BMT的反应，并确定这些不同方法之间的协同机制。2)我们将确定针对INCL不同方面的治疗组合的疗效。

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 9 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 little or 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, histological, or clinical 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 more completely characterize the response of INCL mice to AAV2/5 and BMT and determine the mechanism of synergy between these disparate approaches. 2) We will determine the efficacy of therapeutic combinations that target different aspects of INCL.