KRABBE DISEASE--MOLECULAR ANALYSIS AND TREATMENT

描述：克拉贝病或球形细胞白质营养不良症(GLD)是一种 由基因缺失引起的严重常染色体隐性遗传病 半乳糖脑苷酶(GALC)活性。这导致了不充分的 半乳糖脂的分解代谢对健康、稳定的生产至关重要 髓鞘。尽管大多数患者在6个月前出现症状 并在15个月内死亡，年龄较大的患者也会被确诊。唯一的治疗方法 目前可用的是异体骨髓移植(BMT)。 这种疾病有三种很有特点的自然发生的动物模型， 颤栗鼠、恒河猴、凯恩和西高地白 小猎犬。随着人类、小鼠、猴子和狗GALC基因的克隆， 已发现致病突变和多态突变。 最近的发现，包括非常高的多态发生率 GALC活性低(正常的10-25%)个体的GALC基因 和未诊断的脑白质疾病，以及构建 表达高水平GALC活性的逆转录病毒载体，领导温格博士 提出了以下目标：1.继续分子表征 大量患者的GALC基因突变 他。该基因的所有区域都将被扩增和测序。2.按顺序 为了研究遗传低度但不是完全缺陷的影响， GALC活性，他们计划产生一只具有类似变化的转基因小鼠 并对它们进行生化、病理和临床检查。他会的 检查髓鞘，以及其在实验后再髓鞘形成的能力 脱髓鞘(用铜试剂和溶血磷脂治疗)。3.探索 利用逆转录病毒载体将GALC基因转移到不同类型的细胞中 为邻近的细胞提供酵素。4.饲养受影响的凯恩梗 探索包括宫内和异体骨髓移植在内的治疗方案，以及 应用逆转录病毒转导的造血干细胞进行自体骨髓移植。 这些研究将大大提高对GLD的认识，并为 为未来成功治疗人类患者奠定了基础。

DESCRIPTION: Krabbe disease or globoid cell leukodystrophy (GLD) is a severe, autosomal recessive disorder caused by a deficiency of galactocerebrosidase (GALC) activity. This results in the inadequate catabolism of galactolipids important for the production of healthy, stable myelin. Although most patients present with symptoms before 6 months of age and die by 15 months, older patients are also diagnosed. The only treatment available at this time is heterologous bone marryow transplantation (BMT). This disease has three well characterizd naturally occurring animal models, the twitcher mouse, rhesus monkey, and the Cairn and West Highland White terriers. With the cloning of the human, mouse, monkey and dog GALC genes, disease-causing, as well as polymorphic, mutations have been identified. Recent findings, including a very high incidence of multiple polymorphisms in the GALC gene in individuals with low (10-25% of normal) GALC activity and undiagnosed white matter disease, and advances in constructing retroviral vectors expressing high levels of GALC activity, lead Dr. Wenger to propose the following aims: 1. Continue the molecular characterization of mutations in the GALC gene in a large number of patients available to him. All regions of the gene will be amplified and sequenced. 2. In order to investigate the effects of inheriting low, but not totally deficient, GALC activity, they plan to generate a transgenic mouse with similar changes and examine them biochemically, pathologically and clinically. He will examine the myelin, and its ability to remyelinate after experimental demyelination (by treating with cuprizone and lysolecithin). 3. Explore the use of retroviral vectors to transfer GALC cDNA to various cell types to provide enzyme to neighboring cells. 4. Produce affected Cairn terriers to explore treatment options including in utero and heterologous BMT, and the use of retrovirally transduced hematopoietic stem cells for autologous BMT. These studies will greatly improve the understanding of GLD, and provide the foundation for future attempts to successfully treat human patients.