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.

肌营养不良症是成年人肌营养不良症的主要原因（1：8000）。它是在称为DMPK的基因中重复扩张（突变）引起的，并导致严重的肌肉和心脏病，其寿命明显缩短。没有治疗。我们已经开发了新的反义化合物，这些化合物结合到能够有效地将治疗疗法递送到肌肉组织的蛋白质的短片段中，我们已经证明了这些化合物的能力逆转了小鼠模型中DM1和肌肉细胞引起的恶化的能力。现在，我们将专注于完成铅化合物的临床前开发，并具有最安全的毒理学概况。最近批准了FDA和EMA治疗脊髓肌肉萎缩的寡核苷酸药物Nusinersenby，这标志着主要革新的遗传疾病的开始。 Nusinersen具有重大的临床影响，而否则将死亡的患者保存患者。现在，迫切需要解决类似疾病，这些疾病目前未经治疗，例如DM1。尽管这些疗法在体外工作了几年，但成功完成临床开发的主要挑战是反义化合物是能够将药物输送到组织不动物和患者的组织中。我们的解决方案确实如此，我们开发了一种基于短细胞穿透肽（蛋白质的片段）开发出一种新型的平台技术，该肽在反义分子中提供了非常有效的渗透到细胞中的高效渗透，并且在诸如反义化合物之类的大型药物中很难达到诸如抗浓度的次数，因此很难达到诸如DM1的寿命，因此很难达到诸如抗渗透效率的大型药物。这个20个月计划的最终目标是确定适合于非人类灵长类动物测试的aDRUG。

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.