STUDIES OF GAUCHER DISEASE AND OTHER NEUROGENETIC DISORDERS TOWARD GENE THERAPY

影响人类遗传性疾病的临床病理学相关性 神经系统对于成功发展 诊断技术和治疗策略。 这一目标也是 通过对生物化学和临床的全面了解， 这些疾病的异质性。 戈谢病，最常见的 神经鞘脂病，作为一个模型是非常有用的，因为 神经病性和非神经病性表型的发生。 的 主要类型内广泛的临床多样性的基础 也可以进行研究。 一旦病理生理 这种酶缺乏症的全身参与机制是 了解和治疗，神经系统功能障碍的治疗， 更理性地对待。 葡萄糖脑苷脂酶的基础研究 戈谢病中缺乏的酶，已经产生了一个更详细的 了解结构，生物合成，细胞内，路由，_ 和酶的周转。 这些研究补充了其他研究 在我们的分支内，重点是调查潜在的 基因转移作为一种治疗方法的有效性。 靶向同源 胚胎干细胞中的重组用于开发适当的 戈谢病和其他遗传疾病的转基因动物模型。 转基因奶牛的乳汁中正在产生重组活性酶 动物 人酶和激活蛋白的重组生产 是针对发展有效的替代和基因 转移疗法

Clinical pathological correlations for human genetic disorders affecting the nervous system are important for the successful development of diagnostic techniques and therapeutic strategies. This goal is also facilitated by a comprehensive knowledge of the biochemistry and clinical heterogeneity of these disorders. Gaucher disease, the most common sphingolipidosis, is extremely useful as a model because of the occurrence of both neuronopathic and non-neuronopathic phenotypes. The basis of the broad spectrum of clinical diversity within the major types of the disorder can also be studied. Once the pathophysiologic mechanisms of systemic involvement in this enzyme deficiency disorder are understood and treatable, the therapy of nervous system dysfunction may be more rationally approached. Basic research on glucocerebrosidase, the enzyme deficient in Gaucher disease, has generated a more detailed understanding of the structure, biosynthesis, intracellular, routing,_ and turnover of the enzyme. These studies complement other studies within our branch focusing on the investigation of the potential and efficacy of gene transfer as a therapeutic approach. Targeted homologous recombination in embryonic stem cells is used to develop appropriate transgenic animal models of Gaucher disease and other genetic disorders. Recombinant active enzymes are being produced in the milk of transgenic animals. Recombinant production of human enzymes and activator proteins is directed toward the development of effective replacement and gene transfer therapy.