Optimization of AO drugs 45, 51 & 53

全身递送反义寡核苷酸以驱动外显子跳跃和恢复肌营养不良蛋白表达，作为大多数杜氏肌营养不良症（DMD）患者的治疗剂最有希望。类似的方法也处于SMA和强直性肌营养不良的早期开发阶段。针对DMD的外显子跳跃方法的一个挑战是需要许多针对不同外显子的不同药物。事实上，外显子跳跃被FDA认为是个性化医疗的早期例子，其中药物开发针对特定的患者遗传密码进行优化。这使药物开发过程变得复杂，大大增加了减少DMD患者数量所需的潜在成本和时间。另一种用于流感疫苗的方法是“作为一个类别”批准。适用于最多患者的最初三种AO药物是外显子45、51和53。一旦这三种外显子特异性药物的安全性和有效性得到证明，将外显子跳跃作为一类药物的批准可能有助于不太常见的外显子的药物批准。在这个项目中，我们提出了一个系统的优化外显子45，51和53的AO药物。将使用多个体外和体内实验系统来验证每种药物的效力。轴突45的部分开发过程目前由NIH UOl资助，该项目的PI;该资助项目将扩展到项目3和核心C的患者细胞研究。对于外显子51和53，整个药物开发过程将由拟议的研究计划资助。最后一个目标是在缺乏外显子52的肌营养不良蛋白缺陷小鼠中进行截短肌营养不良蛋白的6个月功能有效性研究，并将测试针对外显子51和53优化的药物。

Systemic delivery of antisense oligonucleotides to drive exon skipping, and restoration of dystrophin expression, has the most promise as a therapeutic for the majority of Duchenne muscular dystrophy (DMD) patients. Similar approaches are also in early stage development for SMA and myotonic dystrophy. A challenge with the exon skipping approach for DMD is the requirement for many distinct drugs targeting different exons. Indeed, exon skipping is being considered by the FDA as an early example of personalized medicine, where drug development is optimized for the specific patient genetic code. This complicates the drug development process, greatly increasing potential cost and time required for diminishing numbers of DMD patients. An alternative approach, used for flu vaccines, is approval 'as a class'. The initial three AO drugs applicable to the greatest number of patients are exons 45, 51, and 53. Once safety and efficacy is proven with these three exon-specific drugs, approval of exon skipping as a class may facilitate drug approvals for less common exons. In this project, we propose a systematic opfimization of AO drugs for exons 45, 51, and 53. Multiple in vitro and in vivo experimental systems will be utilized to validate potency of each drug. Part of the development process for axon 45 is currently funded by a NIH UOl to the PI of this project; this funded program will be extended to patient cell studies from Project 3 and Core C. For exons 51, and 53, the entire drug development process will be funded by the proposed research program. The last aim conducts a 6 month functional efficacy study of the truncated dystrophins in dystrophin-deficient mice lacking exon 52, and will test drugs optimized for both exons 51 and 53.