A Novel Orally Administered Macrophage Delivered Gene Therapy for Gaucher Disease

一种新的口服巨噬细胞传递基因治疗正在开发，以解决目前的问题。 治疗戈谢病的治疗局限性。骨骼和中枢神经系统并发症 戈谢病的发病率仍然对目前的酶和基因替代提出了巨大的挑战 治疗尽管基因治疗策略在动物模型中取得了成功， 迄今为止通常导致低水平的基因表达或移植失败。在这 一项研究中，口服给药的制剂酵母细胞壁颗粒（YCWP）含有DMA编码 人葡糖脑苷脂酶用于恢复巨噬细胞中的人葡糖脑苷脂酶活性， 高雪氏鼠。为了实现这一目标，我们将：1）口服施用含有DNA的YCWP制剂 编码人葡糖脑苷脂酶的小鼠给具有临床表现的长寿L444 P Gaucher小鼠 与戈谢病患者中观察到的相似; 2）确定 处理的戈谢小鼠的巨噬细胞和组织中的酶水平; 3）确定逆转的程度， 脂质储存和组织病理学，以及对生存的影响;以及，4）确定 骨和脑中的巨噬细胞表达人葡糖脑苷脂酶。通过这项研究，我们将 确定将用于人葡糖脑苷脂酶表达的体内优化的参数， 这种口服巨噬细胞的基因疗法。除了改善人的 葡萄糖脑苷脂酶的许多组织，包括骨骼和大脑，我们预计这种方法将实现 在经处理的L444 P Gaucher小鼠中组织病理学的显著逆转。如果巨噬细胞含有人类 当葡萄糖脑苷脂酶迁移到大脑中时，由此产生的酶水平增加可以为 戈谢病的神经学表现这一创新的成功发展 治疗策略应该为患者提供更安全，更有效和成本效益的治疗， 戈谢病，以及提供一个原型的治疗，以造福那些有广泛的其他疾病。 溶酶体疾病

A novel orally administered macrophage delivered gene therapy is being developed to address the present therapeutic limitations in treating Gaucher Disease. The skeletal and central nervous system complications of Gaucher disease still present an enormous challenge for current enzyme and gene replacement therapies. Despite the successes of gene therapy strategies in animal models, the clinical trials conducted to date have generally resulted in either low levels of gene expression or a failure of engraftment. In this study, an orally administered formulation of yeast cell wall particles (YCWP) containing DMA encoding human glucocerebrosidase is used to restore human glucocerebrosidase activity in macrophages of Gaucher mice. To accomplish this goal we will: 1) orally administer formulations of YCWP containing DNA encoding human glucocerebrosidase to long-lived L444P Gaucher mice that have clinical manifestations similar to those observed in patients with Gaucher disease; 2) determine the extent of improvement in enzyme levels in macrophages and tissues of treated Gaucher mice; 3) determine the extent of reversal of lipid storage and tissue pathology, and impact on survival; and, 4) identify the location and degree that macrophages in bone and brain are expressing human glucocerebrosidase. Through this study we will determine parameters that will be used for in-vivo optimization of human glucocerebrosidase expression by this orally administered macrophage delivered gene therapy. In addition to improved delivery of human glucocerebrosidase to many tissues, including bone and brain, we expect that this approach will achieve significant reversal of tissue pathology in treated L444P Gaucher mice. If macrophages containing human glucocerebrosidase migrate into brain, the resulting increased enzyme levels could provide clinical benefit for the neurological manifestations of Gaucher disease. The successful development of this innovative therapeutic strategy should provide a safer, more efficient and cost effective treatment for patients with Gaucher disease, as well as providing a prototype of therapy to benefit those having a wide range of other lysosomal diseases.