Novel Therapies for Globoid-Cell Leukodystrophy

球状细胞脑白质营养不良的新疗法

• 批准号: 8066030
• 负责人: Mark S Sands
• 金额: $ 28.24万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-12 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8066030
• 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; Early treatment; Enzymes; Excision; Exhibits; Functional disorder; Galactose; Galactosylceramides; Globoid cell leukodystrophy; Goals; HIV; Hematopoietic; Histologic; Human; In Vitro; Inflammation Mediators; Inherited; 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

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）：球状细胞脑白质营养不良（GLD，克拉伯病）是一种由溶酶体酶半乳糖脑苷酶（GALC）缺陷引起的脱髓鞘神经退行性疾病。 GLD 影响中枢 (CNS) 和周围 (PNS) 神经系统，其组织学特征是高碘酸希夫 (PAS) 阳性巨噬细胞（球状细胞）的涌入和严重脱髓鞘。婴儿型 GLD 的临床特征是发病较早（三至六个月），伴有烦躁、吞咽困难、痉挛、认知和感觉恶化、癫痫发作，通常在两至三岁时死亡。已经描述了婴儿 GLD 的小鼠模型（Twitcher 小鼠），该模型完全缺乏 GALC 活性，并表现出人类 GLD 的许多生化、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同种异体骨髓移植（BMT）。研究表明，与症状出现后进行的 BMT 相比，在出现症状前的儿童和 Twitcher 小鼠中进行的 BMT 可以显着提高疗效。然而，BMT 只能提供部分缓解，患有 GLD 和 Twitcher 小鼠的儿童仍然患有严重的临床疾病。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，中枢神经系统定向的 AAV2/5 介导的基因治疗和骨髓减退调理后的 BMT 相结合比单独使用任何一种治疗更有效。事实上，这两种不同的方法之间存在着巨大的协同作用。单独使用 BMT、单独使用 AAV2/5 或 AAV2/5 与 BMT 组合治疗的 Twitcher 小鼠的平均寿命分别为 43 天、53 天和 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。这些目标将通过具体目标 1 和具体目标 2 来实现，具体目标 1 量化细胞浸润、炎症介质表达、细胞凋亡以及 Twitcher 小鼠 CNS 和 PNS 中其他组织学变化的时间和空间模式，具体目标 2 确定 CNS 和造血定向基因治疗方法的各种组合的功效。

项目成果

Concise Synthesis of the Unnatural Sphingosine and Psychosine Enantiomer.

非天然鞘氨醇和心理氨酸对映体的简明合成。

• DOI: 10.1002/ejoc.201000024
• 发表时间: 2010
• 期刊: European journal of organic chemistry
• 影响因子: 2.8
• 作者: Parameswar,ArchanaR;Hawkins,JacquelineA;Mydock,LaurelK;Sands,MarkS;Demchenko,AlexeiV
• 通讯作者: Demchenko,AlexeiV