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相关性 神经系统是成功发育的重要因素 诊断技术和治疗策略。这个目标也是 由全面的生物化学和临床知识推动 这些疾病的异质性。高谢病，最常见的 鞘磷脂沉积症作为一个模型是非常有用的，因为 神经病理性和非神经病理性表型均可发生。这个 主要类型中广泛的临床多样性的基础 也可以对这种疾病进行研究。一旦病理生理学 全身性参与这种酶缺乏症的机制是 了解和治疗，神经系统功能障碍的治疗可能 更理性地接近。葡萄糖脑苷酶的基础研究 在高谢病中缺乏酶，已经产生了更详细的 了解结构、生物合成、细胞内、路由、_ 和酶的周转率。这些研究是对其他研究的补充 在我们的分支机构内，专注于对潜在和 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被用来发展适当的 高谢病和其他遗传性疾病的转基因动物模型。 转基因牛乳中正在产生重组活性酶 动物。重组人酶和激活蛋白的生产 旨在开发有效的替代和基因 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.