Novel Therapies for Globoid-Cell Leukodystrophy

描述(申请人提供)：球形细胞白质营养不良症(GLD，Krabbe病)是一种由溶酶体酶半乳糖脑苷酶(GALC)缺乏引起的脱髓鞘神经退行性疾病。GLD同时影响中枢神经系统(CNS)和外周神经系统(PNS)，组织学特征是PAS阳性巨噬细胞(球状细胞)大量涌入和深度脱髓鞘。婴儿型GLD的临床特征是起病早(三到六个月大)，伴有易怒、吞咽困难、痉挛、认知和感觉退化、癫痫发作，通常在两到三岁时死亡。已经描述了一种婴儿GLD(抽动小鼠)的小鼠模型，该模型完全缺乏GALC活性，并表现出许多人类GLD的生化、组织学和临床特征。目前，唯一显示出任何疗效并已用于受影响儿童的治疗方法是异基因骨髓移植(BMT)。研究表明，与在症状出现后进行骨髓移植相比，在症状前儿童和抽动小鼠中进行骨髓移植可以显著提高疗效。然而，骨髓移植只提供了部分反应，患有GLD和Twitcher小鼠的儿童仍然有重大的临床疾病。综上所述，这些数据表明：1)早期诊断和干预是成功治疗这种疾病的关键，2)需要新的创新方法来更有效地治疗这种疾病。研究人员最近表明，中枢神经系统导向的AAV2/5介导的基因治疗与骨髓减少预适应后的骨髓移植相结合比单独使用任何一种治疗方法都更有效。事实上，这两种截然不同的方法之间存在着戏剧性的协同效应。单独接受骨髓移植、AAV2/5或联合应用AAV2/5和BMT的抽动鼠平均存活时间分别为43、53和105天。这项研究的目标是更好地了解疾病的进展，并开发有效的GLD治疗方法。实现这些目标的具体目标1是量化抽动小鼠中枢神经系统和三叉神经节细胞渗透、炎症介质表达、细胞凋亡和其他组织学变化的时间和空间模式，2是确定中枢神经系统和造血导向基因治疗方法的各种组合的疗效。

DESCRIPTION (provided by applicant): Globoid-cell leukodystrophy (GLD, Krabbe disease) is a demyelinating neurodegenerative disorder caused by a deficiency in the lysosomal enzyme galactocerebrosidase (GALC). GLD affects both the central (CNS) and peripheral (PNS) nervous systems, and is characterized histologically by the influx of periodic-acid Schiff (PAS)-positive macrophages (globoid-cells) and profound demyelination. The infantile form of GLD is characterized clinically by an early onset (three to six months of age) with irritability, dysphagia, spasticity, cognitive and sensory deterioration, seizures, and death usually by two to three years of age. A murine model of infantile GLD (Twitcher mouse) has been described which is completely deficient in GALC activity and exhibits many of the biochemical, histological, and clinical features of human GLD. Currently, the only therapeutic approach that has shown any efficacy and has been used in affected children is allogeneic bone marrow transplantation (BMT). It has been shown that BMT performed in both presymptomatic children and the Twitcher mouse can provide dramatically increased efficacy compared to BMT performed after symptoms have developed. However, BMT only provides a partial response and children with GLD and Twitcher mice still have significant clinical disease. Taken together these data suggest that: 1) early diagnosis and intervention are critical for successful treatment of this disease, and 2) new and innovative approaches are required to more effectively treat this disease. The investigators recently showed that a combination of CNS-directed AAV2/5-mediated gene therapy and BMT following myeloreductive conditioning was more effective than either therapy alone. In fact, there was dramatic synergy between these two disparate approaches. Twitcher mice treated with BMT alone, AAV2/5 alone or a combination of AAV2/5 and BMT lived an average of 43, 53, and 105 days, respectively. The goals of this research are to better understand the progression of disease and develop effective therapeutic approaches for GLD. These goals will be accomplished with Specific Aim 1, to quantify the temporal and spatial pattern of cellular infiltration, inflammatory mediator expression, apoptosis, and other histological changes in the CNS and PNS of Twitcher mice, and Specific Aim 2, to determine the efficacy of various combinations of CNS- and hematopoietic-directed gene therapy approaches.