Novel Orally Administered Macrophage Delivered Gene Ther

描述(申请人提供)：一种新的口服巨噬细胞递送基因疗法正在开发中，以解决目前治疗高谢病的治疗局限性。高谢病的骨骼和中枢神经系统并发症对目前的酶和基因替代疗法仍然是一个巨大的挑战。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要么导致低水平的基因表达，要么导致植入失败。在这项研究中，口服含有编码人葡萄糖脑苷酶DNA的酵母细胞壁颗粒(YCWP)来恢复高雪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)向具有与高谢病患者相似的临床表现的长寿L444P高雪鼠口服含有人葡萄糖脑苷酶DNA的YCWP制剂；2)确定经治疗的高谢病小鼠巨噬细胞和组织中酶水平的改善程度；3)确定脂肪储存和组织病理的逆转程度及对生存的影响；以及4)确定骨和脑中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，我们将确定将用于通过口服巨噬细胞递送基因疗法在体内优化人类葡萄糖脑苷酶表达的参数。除了改善人类葡萄糖脑苷酶对许多组织的输送，包括骨骼和脑，我们预计这种方法将在治疗的L444P Gaucher小鼠中实现组织病理的显著逆转。如果含有人类葡萄糖脑苷酶的巨噬细胞迁移到脑内，由此产生的酶水平的升高可能为高谢病的神经学表现提供临床益处。这一创新治疗策略的成功开发将为高谢病患者提供更安全、更有效和更具成本效益的治疗，并提供一个治疗原型，使那些患有广泛其他溶酶体疾病的患者受益。

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.