Inducing Tolerance to Gene Transfer in Dystrophic Mice

描述（由申请人提供）：杜氏肌营养不良症（DMD）是一种由肌营养不良蛋白基因突变引起的遗传性疾病。多年来，基因治疗一直被认为是治疗DMD等遗传性疾病的潜在方法。尽管努力使基因治疗更安全和更适用，宿主对载体和治疗性基因产物的免疫应答仍然被认为是成功基因转移的主要障碍。我们假设，在基因转移之前操纵营养不良小鼠的免疫系统以将肌营养不良蛋白识别为自身组分将导致肌营养不良蛋白在这些小鼠的肌肉中的成功递送和长期表达。我们建议在抗肌萎缩蛋白的存在下扩大Tclad，并将其过继转移到载体受体小鼠中，以诱导这些小鼠中抗肌萎缩蛋白特异性耐受。结果将从平行研究中获得，以研究用高容量腺病毒（HC-Ad）和腺相关病毒（AAV）载体治疗营养不良小鼠之间的差异。这些研究将增强我们对诱导抗原特异性耐受对基因递送的影响的理解，并最终促进肌营养不良蛋白基因成功递送至DMD患者。

DESCRIPTION (provided by applicant): Duchenne Muscular Dystrophy (DMD) is an inherited disorder caused by mutations in the dystrophin gene. For many years gene therapy has been considered a potential way to cure inherited diseases such as DMD. Despite the effort to make gene therapy safer and more applicable, the host immune response to the vector and the therapeutic gene product is still considered a major barrier to successful gene transfer. We hypothesize that manipulating the immune system of dystrophic mice to recognize dystrophin as a self- component before gene transfer will lead to successful delivery and long-term expression of dystrophin in muscles of these mice. We propose to expand Tregs in the presence of dystrophin protein and to adoptively transfer them into vector-recipient mice to induce dystrophin-specific tolerance in these mice. Results will be obtained from parallel studies to investigate the difference between treating dystrophic mice with high- capacity adenoviral (HC-Ad) and adeno-associated viral (AAV) vectors. These studies will enhance our understanding of effects of inducing antigen-specific tolerance on gene delivery and will ultimately facilitate successful delivery of the dystrophin gene to DMD patients.