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)。它是由一种名为DMPK的基因的重复扩展(突变)引起的，会导致严重的肌肉和心脏病，显著缩短寿命。没有治疗方法。我们已经开发出与短蛋白质片段结合的新的反义化合物，能够有效地将治疗传递到肌肉组织，我们已经证明了这些化合物能够逆转DM1在小鼠模型和患者肌肉细胞中引起的恶化。我们现在将专注于完成我们的领先化合物的临床前开发，具有最安全的毒理学特征。最近FDA和EMA批准了寡核苷酸药物Nusinesens用于治疗脊髓性肌萎缩症，标志着遗传病治疗方面的一场重大革命的开始。Nusinesen具有重大的临床影响，并使原本会死亡的患者存活下来。现在迫切需要解决类似的疾病，这些疾病目前没有得到治疗，比如DM1。虽然这些疗法在体外已经工作了几年，但成功完成反义化合物临床开发的主要挑战是能够将药物输送到动物和患者的组织中。我们的解决方案正是做到了这一点，我们开发了一种基于短细胞穿透肽(蛋白质片段)的新平台技术，当它连接到反义分子时，可以高效地渗透到细胞和组织中，如心脏和横隔膜，而反义化合物等大型药物很难到达。这对于有效的治疗至关重要，因为DM1的寿命缩短主要是由于呼吸功能不全和心力衰竭。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身上进行试验的ADGU。

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.