Preclinical Development of Peptide Oligonucleotides for Myotonic Dystrophy Type 1

治疗 1 型强直性肌营养不良的肽寡核苷酸的临床前开发

• 批准号: MR/W014742/1
• 负责人: Matthew Wood
• 金额: $ 100.33万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW014742%2F1
• 关键词: Preclinical; Development; Peptide; Oligonucleotides; Myotonic

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.

肌强直性营养不良是成人肌肉营养不良的主要原因（1:800）。它是由一种名为DMPK的基因的重复扩增（突变）引起的，导致严重的肌肉和心脏疾病，并显著缩短寿命。没有治疗方法。我们已经开发出新的与蛋白质短片段结合的反义化合物，能够有效地将治疗传递到肌肉组织中，我们已经在小鼠模型和患者的肌肉细胞中展示了这些化合物逆转DM1引起的退化的能力。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。最近FDA和EMA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。Nusinersen具有重要的临床影响，使原本会死亡的患者存活下来。现在迫切需要解决目前未得到治疗的类似疾病，如DM1。尽管这些治疗方法已经在体外进行了数年的试验，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这样做的，我们已经开发了一种基于短细胞穿透肽（蛋白质片段）的新平台技术，当它附着在反义分子上时，可以非常有效地渗透到细胞和组织中，如心脏和隔膜，而像反义化合物这样的大型药物很难到达。这对于有效治疗至关重要，因为DM1患者的寿命主要由于呼吸功能不全和心力衰竭而缩短。这个为期20个月的项目的最终目标是确定适合在非人类灵长类动物中进行试验的药物。

项目成果

Application of Antisense Conjugates for the Treatment of Myotonic Dystrophy Type 1.

• DOI: 10.3390/ijms24032697
• 发表时间: 2023-01-31
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Stoodley, Jessica;Vallejo-Bedia, Francisco;Seone-Miraz, David;Debasa-Mouce, Manuel;Wood, Matthew J. A.;Varela, Miguel A.
• 通讯作者: Varela, Miguel A.