METHOD FOR INCREASING GENE THERAPY EFFICACY AND SAFETY

描述(由申请人提供)：本提案的目的是开发 一种安全性和有效性提高的非清髓性调节方案 用于诱导对转基因细胞的特异性免疫耐受。 基因治疗在遗传性和非遗传性疾病治疗中的潜在应用 自身免疫性疾病很普遍，但进展受到了严重的 因免疫反应而引起的疗效下降 转基因产品。混合免疫诱导特异性免疫耐受的研究 造血嵌合体是一种成熟的方法学，可以有效地 重新教育免疫系统，以消除免疫排斥。要实现 异基因干细胞的植入，调节要求是相关的 有毒副作用，移植物抗宿主病是一种常见的副作用。研究 已经证明分子嵌合体可以用来诱导耐受。我们的 初步数据表明，特异性免疫耐受可以诱导到 在自体细胞上表达的单一免疫原蛋白及其调节 分子修饰的自体细胞移植的要求是 低于同种异体移植所需的数量。我们相信， 通过诱导特异性基因治疗可以大大提高基因治疗的有效性 对外来蛋白的免疫耐受被转移，这可能是 使用无毒方案完成。

DESCRIPTION (provided by the applicant): The aim of this proposal is to develop a non-myeloablative conditioning protocol with increased safety and efficacy for the induction of specific immune tolerance to genetically modified cells. Potential applications of gene therapy in the treatment of genetic and autoimmune disorders are widespread, but progress has suffered from a severe reduction in efficacy due to immune reactions raised against therapeutic transgene products. Induction of specific immune tolerance through mixed hematopoietic chimerism is an established methodology that can effectively re-educate the immune system to eliminate immune rejection. To achieve engraftment of allogeneic stem cells, conditioning requirements are associated with toxicities, and graft-versus-host disease is a common side effect. Studies have shown that molecular chimerism can be used to induce tolerance. Our preliminary data suggest that specific immune tolerance can be induced to a single immunogenic protein expressed on autologous cells, and that conditioning requirements for transplantation of molecularly modified autologous cells are less than those required for allogeneic transplants. We believe that the effectiveness of gene therapy can be greatly improved by inducing specific immune tolerance to foreign proteins to be transferred and that this can be accomplished using non-toxic protocols.