KRABBE DISEASE--MOLECULAR ANALYSIS AND TREATMENT

描述：克拉伯病或球样细胞脑白质营养不良（GLD）是一种 一种严重的常染色体隐性遗传疾病，由缺乏 半乳糖苷酶（GALC）活性。 这导致了不充分的 对生产健康、稳定的 髓磷脂 虽然大多数患者在6个月大之前出现症状， 并在15个月内死亡，老年患者也被诊断出来。 唯一的治疗 目前可用的是异源骨髓移植（BMT）。 这种疾病有三种很好的自然发生的动物模型， 抽搐鼠，恒河猴，凯恩和西高地白色 小猎犬 随着人类、小鼠、猴子和狗GALC基因的克隆， 已经鉴定了致病的以及多态的突变。 最近的发现，包括多个多态性的发生率非常高 GALC活性低（正常值的10-25%）个体的GALC基因中 和未确诊的白色疾病，以及在构建 Wenger博士领导的表达高水平GALC活性的逆转录病毒载体 提出以下目标：1. 继续分子表征 GALC基因的突变在大量的患者中， 他 基因的所有区域将被扩增和测序。 2. 为了 研究遗传低，但不是完全缺乏， GALC活性，他们计划产生具有类似变化的转基因小鼠 进行生化病理和临床检查 他将 检查髓鞘，以及实验后髓鞘再生的能力。 脱髓鞘（通过用铜腙和溶血素治疗）。 3. 探索 使用逆转录病毒载体将GALC cDNA转移到各种细胞类型， 为邻近的细胞提供酶。 4. 生产受影响的凯恩梗 探索治疗方案，包括子宫内和异源BMT， 逆转录病毒转导的造血干细胞用于自体BMT的用途。 这些研究将极大地提高对GLD的认识，并提供 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.