Ionis Molecule Shows Early Promise for Myotonic Dystrophy Type 1

High levels of the toxic RNA molecule associated with myotonic dystrophy type 1 (DM1) lead to defects in muscle regeneration and in the number of muscle stem cells — or satellite cells — and promotes muscle fibrosis (scarring) upon injury, according to a study in a mouse model of DM1.

IONIS 877864, Ionis Pharmaceuticals’ investigational therapy targeting this toxic RNA molecule, was found to effectively correct these defects and prevent further muscle damage and fibrosis.

These findings shed light on the damaging effects of the DM1-associated toxic molecule and highlighted the potential of therapies targeting it, such as IONIS 877864.

“The fact that a compound that targets the toxic RNA was beneficial in correcting the poor response to muscle damage is promising,” Mani S. Mahadevan, MD, the study’s senior author and professor of pathology at the University of Virginia (UVA), said in a university press release.

“Many companies are actively developing strategies to target the toxic RNA, and my hope is that one or more of these will be useful as treatments for myotonic dystrophy in the near future,” added Mahadevan, who was one of the discoverers of the gene responsible for DM1.

The study, “Modeling muscle regeneration in RNA toxicity mice,” was published in the journal Human Molecular Genetics.

DM1 is caused by mutations in the DMPK gene, leading to the formation of abnormally long messenger RNA (mRNA) molecules, which form toxic clumps. mRNA is an intermediate molecule derived from DNA that guides protein production.

It’s unclear how this mRNA toxicity causes the progressive muscle loss and its replacement by fat and fibrotic tissue that characterize DM1.

Now, Mahadevan, along with colleagues at the university’s school of medicine and Ionis researchers, provided proof that high levels of this toxic mRNA molecule cause a reduction in the number of satellite cells and impair muscle regeneration.

Satellite cells are key to muscle regeneration in response to damage, and their absence is known to prevent muscle formation at sites of degeneration, resulting in accumulating muscle damage and fibrosis.

By using a mouse model of DM1, developed by Mahadevan and his team, the researchers found that DMPK mRNA toxicity caused a significant drop in the levels of Pax7 — a marker of satellite cells — in the number of satellite cells, and in the levels of MyoD, a marker of muscle maturation, in several of the evaluated muscles.

In addition, these defects were associated with a delay in muscle regeneration and with poor muscle fiber maturation.

Also, repeated muscle damage in these mice led to hallmarks of muscular dystrophy, including fat deposition and increased fibrosis in the muscle. These results represented “one of the first times to model these classic markers of dystrophic changes in the skeletal muscles of a mouse model of RNA toxicity,” the researchers wrote.

“Our ability to study this in a model system helped us uncover the effects on muscle stem cells,” Mahadevan said, adding that “more importantly, it gave us the chance to test if potential treatments aimed at getting rid of the toxic RNA could be beneficial.”

Treating the DM1 mouse model for four weeks with under-the-skin injections of IONIS 877864, an antisense oligonucleotide (ASO) that targets DMPK’s toxic mRNA for degradation, effectively corrected the observed defects in muscle regeneration and in the number of satellite cells.

ASOs are lab-made molecules designed to be complementary to a specific region in the mRNA, either promoting some corrections or targeting it for degradation.

The researchers found that IONIS 877864-treated mice showed a reduction in toxic mRNA clumps, normalization of satellite cell numbers, and an almost complete resolution of induced muscle damage, with formation of large muscle fibers and minimal muscle fibrosis. This was in sharp contrast to mice given a control ASO.

These findings highlighted that DM1-associated defects in muscle regeneration and satellite cells, as well as damage-induced muscle fibrosis, “may be amenable to systemic ASO therapy,” the investigators wrote.

“Importantly, the IONIS 877864 ASO treatment and its efficacy showed clearly that the defects in regenerative response to damage and the defects in satellite cell numbers in the [DM1] mouse model are due to the toxic RNA,” they added.

Mahadevan said the team is continuing to study “the effects of RNA toxicity on various body systems, including muscles and the heart, in hopes of identifying new targets and ways for treatment.”

The tolerability and pharmacological properties of an Ionis’ first-generation ASO targeting DMPK’s toxic mRNA, called IONIS-DMPKRx, were previously evaluated in 48 adults with DM1 in a Phase 1/2 clinical trial (NCT02312011).

Data showed that the therapy failed to reach the target concentration in patients’ muscle samples, prompting Ionis to work on the development of more potent molecules.