Simply Stated: RNA-Based Therapies in Development for Myotonic Dystrophy

Myotonic dystrophy (DM) is a type of muscular dystrophy that affects about 1 in 8,000 people worldwide. DM is characterized by progressive muscle loss and weakness, but can also affect many organs in the body. The non-muscle-related symptoms of DM are variable and often differ from those of other muscular dystrophies. This makes the journey to a diagnosis challenging for people with DM.

There are currently no therapies that can reverse the muscle loss caused by DM, and current treatment primarily aims to manage the symptoms. New therapeutics on the horizon, however, provide hope for people living with DM. The disease is caused by genetic defects within one of several genes, and new methods are being explored to overcome these underlying defects. We review here recent progress in the use of RNA-based therapies as a strategy to treat DM.

The causes and effects of DM

There are two major forms of DM: DM1, also known as Steinert disease, and DM2, recognized as a milder version of DM1. DM1 is caused by a genetic defect, known as an abnormal expansion, within the myotonic dystrophy protein kinase (DMPK) gene, while DM2 is caused by a similar change in the nucleic acid-binding protein (CNBP) gene (also known as ZNF9). The DMPK and CNBP genes encode proteins important for the proper functioning of voluntary muscles used for movement and involuntary muscles, such as the heart or the brain.

Abnormal expansions in the DMPK or CNBP gene results in RNA copies of these genes that have extra, repeated sequences of genetic material (CUG repeats) and cannot be used to make proteins. These defective RNA copies clump together and clog the protein-making machinery. Additionally, they bind to and sequester proteins, such as muscleblind-like (MBNL1), which normally process other RNAs, preparing these messages for protein production. Without the ability to process RNA and make proteins, affected muscle cells cannot function normally. This leads to the signs and symptoms of DM.

DM typically begins in adulthood, usually in a person’s 20s or 30s. A person with DM will likely experience muscle weakness of the skeletal (voluntary) muscles used for movement. A signature feature of DM in many cases is the inability to relax muscles at will (known as myotonia). For example, it may be difficult for someone with DM to let go of an object after gripping it. Many people with DM also experience muscle thinning or loss (atrophy) that gets worse over time.

In addition to muscle issues, DM can also affect the function of a person’s eyes, heart, endocrine system, and central nervous system. People with DM will have some combination of the possible symptoms, with disease severity ranging from mild to life-threatening.

For a general overview of the etiology, symptoms, and progression of DM, see the previous Quest blog post: Simply Stated: What is Myotonic Dystrophy? For an in-depth clinical overview of DM1 and DM2, visit the following links: DM1 GeneReviews and DM2 GeneReviews.

Evolving research and treatment landscape

While the standard of care for DM is symptom management, research is underway to develop disease-modifying treatments. Preclinical research in DM is focused on strategies such as gene-editing technology or small molecules treatment to remove the RNA clumps that are thought to cause DM symptoms. However, these therapies are not yet available for clinical use in humans.

Clinical research into DM is focused in three main areas: (1) therapeutic interventions to block the underlying disease processes, (2) physical/exercise interventions to improve DM symptoms, and (3) observational studies to identify markers of disease and measures that can be used to track improvements in clinical trials.

RNA-based therapies

Within the category of therapeutic interventions in development for DM, RNA-based technologies, specifically antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), have emerged as powerful tools. ASOs are short sequences of single-stranded RNA and siRNAs are short sequences of double-stranded RNA. Both molecules bind specifically to RNA messages and either lead to their destruction or block their ability to bind to other molecules. In the case of DM, these RNA-based therapies are designed to bind to defective DMPK RNA and either reduce toxic RNA clumps or block the sequestration of important proteins such as MBNL1.

Targeting defective RNA molecules with RNA-based therapy has some benefits over other strategies. First, the therapy is less likely to elicit immune responses than gene therapies, which are usually made using viral components. RNA-based therapies are also designed to be specific for particular gene defects and therefore provide more precision than small molecule therapies, which can work non-specifically and lead to unwanted side effects.

A known barrier to the effectiveness of RNA-based therapies is the ability of these molecules to get into the correct cells in the body. One approach to overcome this problem involves the use of peptide-, lipid-, or antibody-based-delivery tags (conjugates) that correctly target the therapies to specific tissues or enable them to enter specific cell types.

Therapeutic development for DM

A number of RNA-based therapies are in clinical development for DM. These include:

ARO-DM1 (Arrowhead Pharmaceuticals) – An siRNA-based therapy designed to reduce levels of the abnormal DMPK RNA in muscle cells. This therapy is being studied in a phase 1/2 clinical trial that is currently recruiting participants.

ATX-01 (arthemiR) (ARTHEx Bioetch S.L.) – A type of ASO that targets a small RNA molecule in the cell (microRNA 23b) that regulates production of MBNL proteins. In preclinical studies, this therapy was shown to both reduce toxic DMPK RNA and increase MBNL protein levels. ATX-01 is being studied in a phase 1/2 clinical trial that is currently recruiting participants.

Del-desiran (formerly AOC-1001) (Avidity Biosciences, Inc.) – An antibody-conjugated siRNA designed to reduce levels of the abnormal DMPK RNA in muscle cells. The antibody portion of del-desiran binds specifically to the transferrin receptor 1 (TfR1), which is highly expressed on muscle cells, improving the targeting of this therapy. Recently published one-year data from the phase 2 MARINA-OLE trial indicated that del-desiran treatment of DM1 patients led to long-term reductions in the severity of myotonia and improvements in muscle strength. Participants are being recruited for the phase 3 HARBOR clinical trial to further assess the safety and effectiveness of del-desiran in people with DM1.

DYNE-101 (Dyne Therapeutics) – An ASO conjugated to an antibody fragment (Fab) that binds to TfR1. DYNE-101 is designed to reduce levels of the abnormal DMPK RNA in muscle cells. Recently published clinical data from the phase 1/2 ACHIEVE trial indicated that DYNE-101 treatment of DM1 patients had positive impacts on key disease biomarkers and reversed disease progression as assessed by multiple tests of muscle strength and function. DYNE-101 continues to be evaluated in the ACHIEVE trial, which is currently recruiting participants. Based on the recent positive data, the sponsor plans to expand the study, with addition of a new cohort, to support a potential submission to the US Food and Drug Administration (FDA) for accelerated approval of the therapy.

PGN-EDODM1 (PepGen) – A peptide-conjugated ASO designed to block abnormal CUG repeats in DMPK RNA, thereby releasing MBNL1 protein and restoring its function. This therapy is currently being evaluated in the ongoing FREEDOM1-DM1 phase 1 (US) and FREEDOM2-DM1 phase 2 (Canada) clinical trials for the treatment of people living with DM1. Both studies are currently recruiting participants.

VX-670 (Vertex Pharmaceuticals) – A peptide-conjugated ASO designed to block abnormal CUG repeats in DMPK RNA, thereby releasing MBNL1 protein and restoring its function. This therapy uses a special Endosomal Escape Vehicle (EEV) technology to increase uptake by cells. VX-670 is being evaluated in a phase 1/2 trial (Galileo) that is currently recruiting participants.

With these RNA-based therapies currently in clinical trials, as well as other therapeutic strategies under investigation, the outlook for achieving an FDA-approved treatment for people with DM looks promising. To learn more about clinical trial and patient registry opportunities in DM1 and DM2, visit clinicaltrials.gov and search for “myotonic dystrophy” in the condition or disease field.

MDA’s Resource Center provides support, guidance, and resources for patients and families, including information about myotonic dystrophy, open clinical trials, and other services. Contact the MDA Resource Center at 1-833-ASK-MDA1 or ResourceCenter@mdausa.org.