Optimization of AO drugs 45, 51 & 53

AO药物的优化 45, 51

• 批准号: 8102467
• 负责人: Qi L Lu
• 金额: $ 24.17万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8102467
• 关键词: Affect; Antisense Oligonucleotides; Axon; Biochemical; Biological Markers; Biopsy; Birth; Cell Culture Techniques; Cells; Clinical Trials; Development; Disease; Drug Approval; Drug Delivery Systems; Duchenne muscular dystrophy; Dystrophin; Exons; Fibroblasts; Funding; Future; Genes; Genetic Code; Grant; Human; In Vitro; Introns; Life; Medicine; Methods; Modality; Mus; Muscular Dystrophies; Mutation; Myoblasts; Myotonic Dystrophy; Patients; Pharmaceutical Preparations; Process; Reporter; Research; Safety; Screening procedure; Skin; Staging; Subgroup; System; Testing; Therapeutic; Time; Translational Research; United States National Institutes of Health; base; cost; drug development; drug testing; in vivo; influenza virus vaccine; male; mouse model; preclinical study; programs; restoration; therapeutic target

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.

全身递送反义寡核苷酸以驱动外显子跳动和恢复肌营养不良蛋白的表达，这是大多数Duchenne肌肉营养不良（DMD）患者的治疗方法。 SMA和肌发育症的早期发展也有类似的方法。 DMD外显子跳过方法的挑战是针对许多针对不同外显子的不同药物的要求。的确，FDA将跳过外显子跳过是个性化医学的早期例子，在该医学中，为特定的患者遗传密码优化了药物开发。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。一种用于流感疫苗的替代方法是“作为一类”的批准。最初适用于最大患者的AO药物是外显子45、51和53。一旦通过这三种外显子特异性药物证明了安全性和疗效，批准外显子跳过为班级可能会促进较不常见的外显子的药物批准。在这个项目中，我们提出了针对外显子45、51和53的AO药物进行系统的操作。将利用多个体外和体内实验系统来验证每种药物的效力。目前，Axon 45的开发过程是由NIH UOL资助的该项目的PI；该资助的程序将扩展到项目3和CoreC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。最后一个目标对缺乏外显子52的肌营养不良蛋白缺陷型小鼠进行了为期6个月的功能疗效研究，并将测试针对外显子51和53优化的药物。