Novel Therapies for Globoid-Cell Leukodystrophy

描述（由申请方提供）：球样细胞脑白质营养不良（GLD，Krabbe病）是一种由溶酶体酶半乳糖苷酶（GALC）缺乏引起的脱髓鞘神经退行性疾病。GLD影响中枢（CNS）和外周（PNS）神经系统，并且在组织学上特征在于β-酸性Schiff（PAS）阳性巨噬细胞（球状细胞）的流入和深度脱髓鞘。婴儿形式的GLD的临床特征为早期发作（3至6个月大），伴有易怒、吞咽困难、痉挛、认知和感觉退化、癫痫发作和通常在2至3岁时死亡。已经描述了婴儿GLD的鼠模型（Twitch小鼠），其完全缺乏GALC活性并且表现出人GLD的许多生化、组织学和临床特征。目前，唯一的治疗方法，已显示出任何疗效，并已被用于受影响的儿童是异基因骨髓移植（BMT）。已经表明，与症状出现后进行的BMT相比，在症状前儿童和Twitch小鼠中进行的BMT可以提供显著增加的疗效。然而，BMT仅提供部分反应，患有GLD和Twitch小鼠的儿童仍然具有显著的临床疾病。这些数据表明：1）早期诊断和干预对于成功治疗这种疾病至关重要，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，CNS指导的AAV 2/5介导的基因治疗和骨髓抑制预处理后的BMT的组合比单独治疗更有效。事实上，这两种截然不同的方法之间存在着巨大的协同作用。用单独的BMT、单独的AAV 2/5或AAV 2/5和BMT的组合处理的Twitcher小鼠分别平均存活43、53和105天。这项研究的目的是更好地了解疾病的进展，并为GLD开发有效的治疗方法。这些目标将通过特定目标1和特定目标2来实现，特定目标1用于量化Twitch小鼠CNS和PNS中细胞浸润、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，特定目标2用于确定CNS和造血定向基因治疗方法的各种组合的功效。

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.