Novel Orally Administered Macrophage Delivered Gene Ther

新型口服巨噬细胞传递基因疗法

• 批准号: 7022537
• 负责人: EDWARD I GINNS
• 金额: $ 32.86万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7022537
• 关键词: Gaucher' s disease; brain; cell transplantation; enzyme therapy; gene delivery system; gene therapy; genetic promoter element; genetically modified animals; glucosylceramidase; histopathology; laboratory mouse; macrophage; microcapsule; nonhuman therapy evaluation; oral administration; protein localization; transfection /expression vector; yeasts

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.

描述（由申请人提供）：正在开发一种新的口服巨噬细胞递送基因疗法，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低水平的基因表达或植入失败。在这项研究中，口服酵母细胞壁颗粒（YCWP）含有编码人葡糖脑苷脂酶的DNA的配方用于恢复戈谢小鼠巨噬细胞中的人葡糖脑苷脂酶活性。为了实现这一目标，我们将：1）将含有编码人葡糖脑苷脂酶的DNA的YCWP制剂口服给药于具有与在患有戈谢病的患者中观察到的临床表现相似的临床表现的长寿L444 P戈谢小鼠; 2）确定经治疗的戈谢小鼠的巨噬细胞和组织中酶水平的改善程度; 3）确定脂质储存和组织病理学逆转的程度，以及对存活的影响;以及，4）鉴定骨和脑中巨噬细胞表达人葡糖脑苷脂酶的位置和程度。通过这项研究，我们将确定参数，将用于在体内优化的人葡糖脑苷脂酶表达的口服巨噬细胞传递基因治疗。除了改善人葡萄糖脑苷脂酶向许多组织（包括骨和脑）的递送外，我们预计这种方法将在治疗的L444 P高雪氏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脂酶的巨噬细胞迁移到大脑中，则导致的酶水平升高可能为戈谢病的神经学表现提供临床获益。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，并提供治疗原型，使患有各种其他溶酶体疾病的患者受益。