Preclinical Development of Peptide Oligonucleotides for Myotonic Dystrophy Type 1

Myotonic Dystrophy is the leading cause of muscular dystrophy in adults (1:8000). It is caused
by a repeat expansion (mutation) in a gene called DMPK and results in severe muscle and
heart disease, with significantly shortened life span. There is no treatment. We have
developed new antisense compounds conjugated to short fragments of proteins able to deliver
the therapy efficiently into muscle tissue, and we have shown the ability of these compounds
to reverse the deterioration caused by DM1 in mouse models and in muscle cells derived from
patients. We will now focus on completing the preclinical development of our lead compound
with the safest toxicology profile. The recent approval of the oligonucleotide drug Nusinersen
by the FDA and EMA for treatment of spinal muscular atrophy marks the start of a major
revolution in the treatment of genetic diseases. Nusinersen has major clinical impact and
keeps patients alive who would otherwise have died. There is now urgent need to address
similar diseases which are currently untreated like DM1. Although these kinds of therapies
have worked in vitro for several years the major challenge to successfully complete the clinical
development an antisense compound is to being able to deliver the drug to the tissues in
animals and patients. Our solution does exactly that, we have developed a novel platform
technology based on short cell penetrating peptides (fragments of proteins), which when
attached to the antisense molecule provide highly effective penetration into cells and into
tissues 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 respiratory
insufficiency and cardiac failure. The final goal of this 20-month programme is to identify a
drug suitable for testing in non-human primates.

Myotonic Dystrophy 1 (DM1) is the leading cause of muscular dystrophy in adults (1:8000)
globally. It is caused by a repeat expansion in the gene DMPK and results in severe muscle
and heart disease, with significantly shortened life span. There are no disease-modifying
therapies. We have developed a novel platform technology based on short cell penetrating
peptides, which when attached to the antisense molecule provide highly effective penetration
into cells and tissues such as heart. Difficulty in approaching such tissues is a major caveat
for large drugs like antisense compounds. However, we have shown the ability of these
antisense compounds to reverse the deterioration caused by DM1 in mice, and in cells from
patients. Recent approval of the oligonucleotide drug Nusinersen by the FDA and EMA for
treatment of spinal muscular atrophy marks the start of a major revolution in the treatment of
genetic diseases. Nusinersen has major clinical impact and keeps patients alive who would
otherwise have died. There is now urgent need to address similar diseases which are currently
untreated like DM1. The major challenge in the field is to deliver the drug at an appropriate
dose to the tissues in vivo which demonstrates therapeutic effect. Our solution does exactly
that, and a unique distinction of our peptide-conjugated antisense compounds is that they can
penetrate cardiac tissue which is critical for effective therapy since life span in patients is
reduced primarily due to cardiac failure. For this reason, we would like to study in detail the
effects of our lead compounds in the electrophysiology and transcriptome of cardiomyocytes
derived from DM1 patient iPS cells, and in vivo in DM1 mice. The final goal of this 20-month
programme is to identify a lead antisense compound suitable for testing in non-human
primates and subsequent clinical development.