Preclinical Development of Peptide Oligonucleotides for Myotonic Dystrophy Type 1

强直性肌营养不良症是成人肌营养不良症的主要原因（1：8000）。它是由一种叫做DMPK的基因的重复扩增（突变）引起的，并导致严重的肌肉和心脏疾病，寿命显着缩短。没有治疗方法。我们已经开发出了新的反义化合物结合到短片段的蛋白质，能够有效地提供治疗到肌肉组织，我们已经证明了这些化合物的能力，以扭转恶化所造成的DM1在小鼠模型和肌肉细胞从病人。我们现在将专注于完成我们的先导化合物的临床前开发，具有最安全的毒理学特征。FDA和EMA最近批准寡核苷酸药物Nusinersen用于治疗脊髓性肌萎缩症，标志着遗传性疾病治疗的重大革命的开始。诺西那生具有重大的临床影响，可使原本可能死亡的患者存活。现在迫切需要解决类似的疾病，目前未经治疗的DM1。虽然这些种类的治疗已经在体外工作了几年，但成功完成临床开发的主要挑战是反义化合物能够将药物递送到动物和患者的组织中.我们的解决方案正是这样做的，我们开发了一种基于短细胞穿透肽的新型平台技术（蛋白质片段），当连接到反义分子上时，可以高效地渗透到细胞和组织中，如心脏和隔膜，这对于有效的治疗是至关重要的，因为DM 1的寿命缩短主要是由于代谢功能不全和心血管疾病。失败这项为期20个月的计划的最终目标是确定适合在非人类灵长类动物中进行测试的药物。

Myotonic Dystrophy is the leading cause of muscular dystrophy in adults (1:8000). It is causedby a repeat expansion (mutation) in a gene called DMPK and results in severe muscle andheart disease, with significantly shortened life span. There is no treatment. We havedeveloped new antisense compounds conjugated to short fragments of proteins able to deliverthe therapy efficiently into muscle tissue, and we have shown the ability of these compoundsto reverse the deterioration caused by DM1 in mouse models and in muscle cells derived frompatients. We will now focus on completing the preclinical development of our lead compoundwith the safest toxicology profile. The recent approval of the oligonucleotide drug Nusinersenby the FDA and EMA for treatment of spinal muscular atrophy marks the start of a majorrevolution in the treatment of genetic diseases. Nusinersen has major clinical impact andkeeps patients alive who would otherwise have died. There is now urgent need to addresssimilar diseases which are currently untreated like DM1. Although these kinds of therapieshave worked in vitro for several years the major challenge to successfully complete the clinicaldevelopment an antisense compound is to being able to deliver the drug to the tissues inanimals and patients. Our solution does exactly that, we have developed a novel platformtechnology based on short cell penetrating peptides (fragments of proteins), which whenattached to the antisense molecule provide highly effective penetration into cells and intotissues such heart and diaphragm, difficult to reach for large drugs like antisense compounds.This is critical for effective therapy since life span in DM1 is reduced primarily due to respiratoryinsufficiency and cardiac failure. The final goal of this 20-month programme is to identify adrug suitable for testing in non-human primates.