Preclinical Development of Peptide Oligonucleotides for Myotonic Dystrophy Type 1

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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.