#AANAM – Investigational DM1 Therapy Shows Promise

Editor’s note: The Muscular Dystrophy News Today team is providing in-depth coverage of the 2021 Virtual AAN Annual Meeting, April 17–22. Go here to read the latest stories from the conference.

An investigational therapy called AOC-1001 decreased levels of the toxic RNA molecule that causes myotonic dystrophy type 1 (DM1) in cell and animal models of the disease.

Avidity Biosciences expects to start clinical studies testing the potential therapy later this year.

The findings were shared in the presentation, “Optimization of AOC-1001, an antibody-oligonucleotide conjugate targeting the underlying cause of myotonic dystrophy type 1,” (page 26) at this year’s American Academy of Neurology Annual Meeting (AANAM).  The meeting is being held online April 17–22.

DM1 is caused by mutations in the gene DMPK. Like most genes, DMPK is essentially a set of instructions encoded in the cell’s DNA that tells the cell how to make a protein. When the gene is “read,” the code in the DNA is copied into an RNA molecule (called messenger RNA, or mRNA), which is then transported to the cell’s protein-making machinery so the protein can be made.

In DM1, mutations in DMPK result in the formation of an abnormally long mRNA molecule. This extra-long mRNA is toxic to cells, forming abnormal clumps with other cellular components.

In theory, decreasing levels of mutant DMPK mRNA could be a therapeutic strategy for DM1. One potential way to do this is by using short interfering RNA (siRNA) — a specialized kind of RNA molecule that is able to bind to mRNA with a particular genetic sequence, a bit like how a key fits into its specific lock. When siRNA binds its target mRNA, that mRNA is targeted for destruction by the cell.

“siRNA can be used to target the toxic DMPK mRNA for degradation, and therefore treat the underlying cause of DM1,” Barbora Malecova, PhD, associate director at Avidity, said at AANAM.

In order to be effective, siRNA need to get inside a cell. Generally, siRNA molecules alone cannot get into living cells, which has limited their clinical utility. AOC-1001 is a new investigational medication that attempts to solve this problem by attaching an siRNA targeting the DMPK mRNA to an antibody.

Simply put, the antibody binds to a protein receptor on the surface of a cell. This induces a process called receptor-mediated endocytosis through which the siRNA enters the cell to exert its effect on the target mRNA.

“Avidity is developing AOC-1001 for the treatment of DM1 that allows for efficient delivery of [siRNA] into muscle and heart tissue,” Malecova said.

In myoblasts (precursor cells of skeletal muscle) derived from DM1 patients, treatment with AOC-1001 significantly reduced levels of toxic DMPK mRNA — by 60% in the nucleus and by 80% in the cytoplasm (the cell interior except the nucleus). Consistently, the abnormal clumping activity induced by this toxic mRNA was significantly reduced.

These data demonstrate “the ability of [the siRNA] to target the underlying molecular cause of DM1,” Malecova said,

In non-human primates (cynomolgus monkeys), treatment with a single infusion of AOC-1001 significantly reduced levels of DMPK mRNA in muscles: at a dosage of 2 mg/kg, the investigational therapy reduced toxic mRNA levels by about 75%, and this reduction was maintained for at least 12 weeks. A similar decrease was found in the heart and other tissues four weeks after a 6 mg/kg dose.

The data demonstrate “the robust, durable activity of AOC-1001 in vivo [in living animals] in muscles of non-human primates,” Malecova concluded. “AOC-1001 is a potential DM1 disease-modifying therapy.”

Avidity is planning to launch clinical studies of the investigational medication in the second half of this year, according to Malecova.