Novel Therapies for Globoid-Cell Leukodystrophy

球状细胞脑白质营养不良的新疗法

基本信息

批准号：
8080001
负责人：
Mark S Sands
金额：
$ 10.66万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-10 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8080001
关键词：
3 year old Affect Age Age-Months Age-Years Allogeneic Bone Marrow Transplantation Apoptosis Biochemical Bone Marrow Transplantation Cells Cellular Infiltration Ceramides Cessation of life Child Clinical Cognitive Data Deglutition Disorders Demyelinations Deterioration Disease Disease Progression Early Diagnosis Enzymes Excision Exhibits Functional disorder Galactose Galactosylceramides Globoid cell leukodystrophy Goals HIV Hematopoietic Histologic Human In Vitro Inflammation Mediators Inherited Intervention Intrathecal Injections Life Limb structure Longevity Mediating Metabolic Diseases Modeling Motor Mus Myelin Nervous system structure Neurodegenerative Disorders Oligodendroglia Outcome Measure Paralysed Pathogenesis Pattern Periodic acid Schiff stain method Peripheral Proteins Psychosine Research Research Personnel Seizures Sensory Silicon Dioxide Staging Symptoms Therapeutic Time advanced disease comparative efficacy conditioning early onset galactosylceramidase gene therapy in vivo infancy innovation macrophage novel partial response programs

3 year old Affect Age Age-Months Age-Years Allogeneic Bone Marrow Transplantation Apoptosis Biochemical Bone Marrow Transplantation Cells Cellular Infiltration Ceramides Cessation of life Child Clinical Cognitive Data Deglutition Disorders Demyelinations Deterioration Disease Disease Progression Early Diagnosis Enzymes Excision Exhibits Functional disorder Galactose Galactosylceramides Globoid cell leukodystrophy Goals HIV Hematopoietic Histologic Human In Vitro Inflammation Mediators Inherited Intervention Intrathecal Injections Life Limb structure Longevity Mediating Metabolic Diseases Modeling Motor Mus Myelin Nervous system structure Neurodegenerative Disorders Oligodendroglia Outcome Measure Paralysed Pathogenesis Pattern Periodic acid Schiff stain method Peripheral Proteins Psychosine Research Research Personnel Seizures Sensory Silicon Dioxide Staging Symptoms Therapeutic Time advanced disease comparative efficacy conditioning early onset galactosylceramidase gene therapy in vivo infancy innovation macrophage novel partial response programs

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项目摘要

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.

描述（由申请人提供）：Globoid-Cell白细胞营养不良（GLD，Krabbe疾病）是由溶酶体酶半乳糖苷酶（GALC）缺乏引起的神经退行性疾病。 GLD会影响中心（CNS）和周围（PNS）神经系统，并以周期性 - 酸Schiff（PAS）阳性巨噬细胞（Globoid-Cells）和深刻的脱髓鞘的流入为特征。 GLD的婴儿形式在临床上以早期发作（三到六个月大）的特征，烦躁，吞咽困难，痉挛，认知和感觉降解，癫痫发作和死亡通常在两到三岁。已经描述了一种婴儿GLD（Twitcher小鼠）的鼠模型，该模型在GALC活性中完全不足，并展示了人类GLD的许多生化，组织学和临床特征。当前，唯一显示出任何功效并已在受影响儿童中使用的治疗方法是同种异体骨髓移植（BMT）。已经表明，与症状发生后进行的BMT相比，在预症状儿童中进行的BMT和Twitcher小鼠可以显着提高疗效。但是，BMT仅提供部分反应，患有GLD的儿童和Twitcher小鼠仍然患有明显的临床疾病。综上所述这些数据表明：1）早期诊断和干预对于成功治疗该疾病至关重要，2）需要更有效地治疗该疾病的新方法和创新方法。研究人员最近表明，在骨髓调节性调节后，CNS定向的AAV2/5介导的基因疗法和BMT的结合比单独使用任何一种治疗更有效。实际上，这两种不同的方法之间存在着戏剧性的协同作用。单独使用BMT治疗的Twitcher小鼠，单独使用AAV2/5或AAV2/5和BMT的组合平均寿命分别为43、53和105天。这项研究的目标是更好地了解疾病的进展，并为GLD开发有效的治疗方法。这些目标将通过特定目标1实现，以量化细胞浸润的时间和空间模式，炎症介质表达，凋亡，凋亡以及Twitcher小鼠的CNS和PNS中的其他组织学变化，并确定CNS和血型和血肿的基因疗法的各种组合的效率。