Myotonic Dystrophy Researcher Receives Award

  • Images

    • The Barry M. Goldwater Scholarship and Excellence in Education Program was established by Congress in 1986 to honor Goldwater, who served 30 years in the U.S. Senate.

      The Barry M. Goldwater Scholarship and Excellence in Education Program was established by Congress in 1986 to honor Goldwater, who served 30 years in the U.S. Senate.

blog posts

  • Editor’s note: For more information, contact David Schug, National and International Scholarships Program director, 217-333-4710, email

Another study advancing a potential treatment of myotonic Dystrophy

This is a fairly scientific study of using the CRISPER Technology to help find a treatment for myotonic dystrophy. DM1 is caused by expanded CTG repeats in the 30 UTR. It is conceivable that simply deleting the expanded CTG repeats may cure the disease. With the advancement of therapeutic genome-editing technologies, this is becoming more realistic.


Press Release about Cugamycin that might treat Myotonic Dystrophy in Future


New therapy targets cause of adult-onset muscular dystrophy

Animal study shows no off-target effects of RNA-based therapy





JUPITER, Fla. – April 1, 2019 — People diagnosed with myotonic dystrophy type 1 have difficulty unclenching muscles due to a genetic defect that generates toxic material within their cells. There is currently no treatment. In a new report published in the Proceedings of the National Academy of Sciences on Monday, a group at Scripps Research in Florida reports making a potential drug that targets its key disease-causing RNA. In mouse and cellular models of myotonic dystrophy type 1, it improved the muscle defects with no apparent side-effects.

The study appeared on line Friday in PNAS. More work lies ahead before testing in people will be possible, but “the results look better than we could have imagined,” says lead author Matthew Disney, PhD, a Scripps Research chemistry professor.

“The results suggest that our technology can be used to treat myotonic dystrophy type 1 and similar categories of inherited diseases, and without unintended, off-target effects,” Disney says, adding, “There is great potential for drugging RNA in all disease settings.”

The most common form of muscular dystrophy in adults, myotonic dystrophy type 1 has been estimated to affect around 1 in 8,000 people, although the Myotonic Dystrophy Foundation, based in San Francisco, reports that misdiagnosis is common, likely leading to underreporting. Genetic studies suggest the actual numbers are more than three times higher, around 1 in 2,500, says Molly White, CEO of the foundation.

The disease is inherited. Symptoms emerge in late teens or early adulthood as genetic changes accumulate. They include muscle clenching, lock-jaw, early-onset cataracts, brain fog, muscle wasting and weakness, digestive difficulties, and sudden cardiac death, White says. Severity and rate of progression depend on factors including the nature of the genetic defect.

Myotonic dystrophy type 1 occurs when a sequence of three nucleotides, CTG, is repeated too many times within a gene called DMPK. Toxic protein clumps generate further genetic defects, resulting in muscle weakness and other symptoms. A healthy person could carry between 5 and 35 repeats of CTG within that gene without experiencing obvious difficulty. But symptomatic people may have 50, 100 or even up to 4,000 repeats of the CTG sequence.

The drug Disney’s group designed, called Cugamycin, works by recognizing the toxic RNA repeats and destroying the garbled gene transcript. Significantly, in treated animals, the drug left the healthy version of the gene transcript intact. The results were consistent in both the mouse model of myotonic dystrophy type 1 and in human patient-derived muscle fibers called myotubes.

Cugamycin was made by attaching an RNA-binding molecule to an existing drug called bleomycin, which cleaves nucleic acids.

“Analysis of the tissue from a pre-clinical disease model showed more than 98 percent of the disease defects are improved, with no detectable off-targets.” Disney says.

So far, the results have been excellent, but these studies are still in their early stages, says Alicia Angelbello, the study’s first author and a Scripps Research graduate student.

“A key next question will be to evaluate the effectiveness of our compound over a longer period of time,” she adds. In the current study, the treated mice experienced fewer instances of “myotonic discharges” in their muscles–occasions when it takes longer than usual for a contracted muscle to relax–compared to untreated mice, Angelbello says.

“Once given the Cugamycin at a dose of 10 milligrams per kilogram, the frequency of the myotonic discharges was reduced by 50 percent, which is a significant improvement,” Angelbello says. “The fact that we can improve the muscular and genetic defects in DM1 mice with the molecules we have made in the lab is a significant step in learning about how to treat this disease,” she says. The Myotonic Dystrophy Foundation has supported Disney’s work for many years.

“Matt Disney is super-committed to making a treatment for this disease,” says White, CEO of the Myotonic Dystrophy Foundation. “It’s clear that many people think his lab is on the right track. We’re thrilled at the progress he is making.”


In addition to Disney and Angelbello, the authors of the study, “Precise small molecule cleavage of an r(CUG) repeat expansion in a myotonic dystrophy mouse model,” include Suzanne Rzuczek, Jonathan Chen and Michael Cameron of Scripps Research; Kendra McKee, Hailey Olafson and Eric Wang of the University of Florida; and Walter Moss of Iowa State University. Disney and Wang consult for Expansion Therapeutics. Rzuczek is an employee of Expansion Therapeutics. Disney’s work was funded by the National Institutes of Health (grant DP1NS096898) and the Muscular Dystrophy Association (grant 380467). The Myotonic Dystrophy Foundation also provided support.

Cuyamycin Molecule looks promising for Myotonic Dystrophy Treatment

A new study published shows that a small molecule (Potential new treatment) disrupted the long CTG repeats but left short repeats mostly alone.This was tested in mice that had myotonic dystrophy and seemed to work well.  Here is a piece form the journal about the impact of this study

Development of small-molecule lead medicines that potently and specifically modulate RNA function is challenging. We designed a small molecule that cleaves r(CUG)exp, the RNA repeat expansion that causes myotonic dystrophy type 1. In cells and in an animal model, the small-molecule cleaver specifically recognizes the 3-dimensional structure of r(CUG)exp, cleaving it more selectively among transcripts containing short, nonpathogenic r(CUG) repeats than an oligonucleotide that recognizes RNA sequence via Watson-Crick base pairing. The small molecule broadly relieves disease-associated phenotype in a mouse model. Thus, small molecules that recognize and cleave RNA structures should be


NIH sponsored research shows promise

April 9, 2019

Small molecule targets cause of adult onset muscular dystrophy


At a Glance

  • Researchers developed a small molecule that, in mice, blocks the mutated RNA responsible for adult onset muscular dystrophy.
  • The findings suggest a new avenue to develop therapeutics for this condition.
Illustration of DNA and RNAMyotonic dystrophy is caused by mutant DNA that results in toxic messenger RNA

Muscular dystrophy includes over 30 inheritable diseases. These are characterized by progressive weakness and degeneration of the muscles. Some types of muscular dystrophy appear in childhood, while others may not appear until adulthood.

Myotonic dystrophy is the most common form of adult onset muscular dystrophy. People with this disorder experience a delay in relaxing their muscles after using them. Type 1 usually affects the lower legs, hands, neck, and face; whereas, type 2 typically affects the neck, shoulders, elbows, and hips. They are caused by mutations in different genes.

Type 1 is caused by a mutation in the dystrophia myotonica protein kinase (DMPK) gene. This mutation causes three nucleotides, CTG, to repeat multiple times in the gene’s DNA. Most people have between 5 to 34 CTG repeats in this gene; however, people with type 1 myotonic dystrophy have from 50 to 5,000.

These extra repeats result in a toxic messenger RNA (mRNA) that traps proteins and forms clumps within cells. This interferes with many important proteins that regulate muscle gene products, leading to serious defects in the muscle cells.

To test whether a small molecule could target the altered RNA and block it from trapping proteins, a team led by Dr. Matthew Disney at Scripps Research Institute carried out experiments in muscle cells taken from patients with myotonic dystrophy type 1 and a mouse model of the disease. The research was supported in part by NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and an NIH Director’s Pioneer Award. Results were published online on March 29, 2019, in the Proceedings of the National Academies.

The researchers designed a small molecule to specifically target the altered RNA’s 3D structure, which folds into a hairpin shape. They first tested its activity in cells taken from patients with myotonic dystrophy. The molecule, called Cugamycin, cleaved 40% of the DMPKmRNA in cells taken from patients, but not in healthy control cells. It also reduced the mRNA’s binding to MBNL1, an important protein it commonly traps, by about 30%.

The team then tested the molecule in a mouse model of myotonic dystrophy type 1 that has 250 CTG repeats. Mice were treated with Cugamycin every other day for one week. Treated mice showed 40% less of the mutated mRNA in their lower leg muscles than untreated mice. They also showed partial improvement in their ability to relax their lower leg muscles.

The toxic mRNA from the mutated DMPK gene alters the expression of 326 genes in this mouse model. Cugamycin treatment restored the normal expression of 177 of these. In an analysis of more than 15,000 other genes, the researchers found no off-target effects.

“The results suggest that our technology can be used to treat myotonic dystrophy type 1 and similar categories of inherited diseases, and without unintended, off-target effects,” Disney says.

These findings demonstrate that small molecules can be designed to selectively target and destroy mutated RNA molecules that cause human disease. However, more studies are needed before this molecule could be tested in people.

—by Tianna Hicklin, Ph.D.

Continue reading