A Novel Orally Administered Macrophage Delivered Gene Therapy for Gaucher Disease

描述（由申请人提供）：一种新的口服巨噬细胞传递基因疗法正在开发中，以解决目前治疗戈谢病的治疗局限性。戈谢病的骨骼和中枢神经系统并发症仍然是目前酶和基因替代疗法的巨大挑战。尽管基因治疗策略在动物模型中取得了成功，但迄今为止进行的临床试验通常导致基因表达水平低或植入失败。在这项研究中，一种含有编码人葡萄糖脑苷酶DNA的酵母细胞壁颗粒（YCWP）口服制剂被用于恢复高切小鼠巨噬细胞中人葡萄糖脑苷酶的活性。为了实现这一目标，我们将：1)口服含有编码人葡萄糖脑苷酶DNA的YCWP制剂给具有与戈谢病患者相似临床表现的长寿L444P戈谢病小鼠；2)测定高歇小鼠巨噬细胞和组织中酶水平的改善程度；3)确定脂质储存逆转程度和组织病理，以及对生存的影响；4)确定骨和脑巨噬细胞表达人葡萄糖脑苷酶的位置和程度。通过这项研究，我们将确定一些参数，这些参数将用于通过口服巨噬细胞传递基因疗法优化人葡萄糖脑苷酶的体内表达。除了改善人类葡萄糖脑苷酶向许多组织（包括骨和脑）的递送外，我们期望这种方法将在治疗过的L444P Gaucher小鼠中实现组织病理学的显著逆转。如果含有人葡萄糖脑苷酶的巨噬细胞迁移到大脑中，由此导致的酶水平升高可能为戈谢病的神经学表现提供临床益处。这种创新治疗策略的成功开发应该为戈谢病患者提供更安全、更有效和更具成本效益的治疗，并为患有各种其他溶酶体疾病的患者提供治疗的原型。

DESCRIPTION (provided by applicant): 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 DNA 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.