A Novel Orally Administered Macrophage Delivered Gene Therapy for Gaucher Disease

一种新型口服巨噬细胞治疗戈谢病的基因疗法

• 批准号: 7340503
• 负责人: EDWARD I GINNS
• 金额: $ 31.95万
• 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/7340503
• 关键词: Address; Animal Model; Brain; Cell Wall; Cells; Clinical; Code; Conduct Clinical Trials; DNA; Development; Disease; Drug Formulations; Engraftment; Enzyme Gene; Enzymes; Failure; Gaucher Disease; Gene Expression; Goals; Human; In Vitro; Life; Lipids; Location; Microspheres; Mus; Neuraxis; Neurologic Manifestations; Pathology; Patients; Production; Range; Replacement Therapy; Research Personnel; Skeletal system; Therapeutic; Time; Tissues; Yeasts; bone; cost effective; enzyme activity; gene replacement; gene therapy; glucosylceramidase; improved; in vivo; innovation; macrophage; novel; particle; programs; promoter; prototype; restoration; success; vector

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.

一种新的口服巨噬细胞递送基因疗法正在开发中，以解决目前的问题 治疗高谢病的治疗局限性。骨骼和中枢神经系统并发症 对于目前的酶和基因替代来说，仍然是一个巨大的挑战 治疗。尽管基因治疗策略在动物模型中取得了成功，但临床试验仍在进行 到目前为止，通常要么导致基因表达水平低，要么导致植入失败。在这 研究，一种含有DMA编码的酵母细胞壁颗粒(YCWP)口服制剂 人葡萄糖脑苷酶用于恢复人巨噬细胞中的葡萄糖脑苷酶活性 高雪鼠。为了实现这一目标，我们将：1)口服含有DNA的YCWP制剂 对有临床症状的长寿L444P-Gaucher小鼠编码人脑糖苷酶 与在高谢病患者中观察到的相似；2)确定 高雪鼠巨噬细胞和组织中的酶水平；3)决定 脂肪储存和组织病理，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萄糖脑苷酶。通过这项研究，我们将 通过以下方法确定用于体内优化人脑糖苷酶表达的参数 这种口服巨噬细胞递送的基因疗法。除了改进人的交付之外 葡萄糖脑苷酶对许多组织，包括骨骼和大脑，我们预计这种方法将实现 治疗后L444P-Gaucher小鼠的组织病理学显著逆转。如果巨噬细胞含有人类 葡萄糖脑苷酶迁移到大脑，由此产生的酶水平增加可能为临床提供好处 高谢病的神经学表现。这一创新技术的成功开发 治疗策略应为以下患者提供更安全、更有效和更具成本效益的治疗 高谢病，以及提供一个治疗原型，使那些患有广泛其他疾病的人受益 溶酶体疾病。