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Highlights from IDMC-10

MDF Executive Director Molly White and Research Director Sharon Hesterlee recently attended the tenth meeting of the International Myotonic Dystrophy Consortium in Paris. Over three hundred scientists and representatives from companies and patient organizations participated in the meeting this year, demonstrating the growing interest in myotonic dystrophy research. Sharon has created a report-out to the community on a selection from the more than 160 presentations and posters, to keep you apprised of some of the newest updates and information. Read more below.

Cognition

Benjamin Gallais of the Université de Sherbrook in Quebec presented the results of a nine-year study of cognition in adults with myotonic dystrophy, comparing “classical” onset (symptoms commonly begin in the second or third decade) to late onset (symptoms begin after the fifth decade). At the beginning of the study, most participants showed some mild impairment in executive function, language and visual memory. Nine years later, the 115 people who completed the study also showed declines in verbal memory, visual attention and processing speed. Language and IQ remained stable. When people with classical onset were compared to people with late onset, some cognitive symptoms progressed more slowly in those with classical onset.

Anne-Berti Ekström of Queen Silvia’s Children’s Hospital at the University of Gothenburg, Sweden, described changes in cognitive and adaptive function (how someone copes with everyday life) in congenital and childhood onset myotonic dystrophy type 1 over a period of about 7 years. Participants were categorized as having severe congenital, mild congenital or childhood forms and almost all had some level of intellectual disability at the start of the study. Her findings suggest that changes in cognitive function are not consistent in that 25% of participants showed a trend for cognitive decline while 12% showed a trend for improvement (the results were not statistically significant). The trend for improvement was seen in those with childhood onset DM. Many participants showed gains in communication skills.

Cancer

Dr. Shahinaz Gadalla of the US National Cancer Institute (NCI) described the rate of brain cancer in people with myotonic dystrophy in Sweden, and compared the results with the NCI cancer registry. Sixteen people with myotonic dystrophy were identified in the Swedish registry who also had brain cancer at any time between 1987 and 2007. When compared to the NCI database, Dr. Gadalla found no difference in tumors by type, but did discover a relative increase of five fold compared to the general population (the absolute risk is still very modest, at 2 in 100 by age 60). Post-diagnosis survival was better for those with myotonic dystrophy than those without. Dr. Gadalla concludes that careful monitoring of people with DM1 who develop new central nervous system symptoms is warranted.

Diagnostic Delay

Also from Sweden, Dr. Christopher Lindberg explored the length of the diagnostic odyssey for DM1 in that country. In a survey of 230 people with 177 respondents, he found that the mean age to diagnosis was 11.7 years. The delay in diagnosis depended on the primary presenting symptom. For example, the delay for those who presented with muscle weakness was 7.6 years, while those who presented with cardiac symptoms received a correct diagnosis within 4 years. People who present first with gastrointestinal symptoms had the longest diagnostic odyssey at 16.6 years. Dr. Lindberg also explored the delay in diagnosis for childhood, classical, and adult late onset (over age 50), and found that the delay was longest for the childhood onset form (15.7 years) and shortest for adult late onset (6.5 years).

Myotonic Dystrophy Family Registry

For the first time, MDF presented a poster with current findings from the Myotonic Dystrophy Family Registry, which currently contains over 1,400 individual entries from 37 countries. The most commonly reported symptoms for both DM1 and DM2 were affected walking ability, fatigue, daytime sleepiness and myotonia. Those with DM1 reported significantly more problems with swallowing, but no other differences in the presence of symptoms between the two groups were found (although the severity of symptoms may be different). Click here to view the poster. Registry data is available to all members, and current registrants are encouraged to update their information if anything has changed. To join or log in to the Registry, click here.

Disease Mechanism

Is there a link between Duchenne muscular dystrophy and myotonic dystrophy? Work presented by Frédérique Rau of the Institute de Myologie at GH Pitié-Salpêtrière in Paris and colleagues demonstrated that one of the genes that is not processed correctly in myotonic dystrophy is “dystrophin” - the same gene that is mutated in Duchenne muscular dystrophy. Dr. Rau and colleagues showed that the form of dystrophin produced by people with myotonic dystrophy is one that is normally only produced during embryonic development, and that mice that are made to have this embryonic form of dystrophin as adults have significant muscle weakness. It’s not yet clear how much the misprocessed dystrophin contributes to muscle weakness in myotonic dystrophy, but the finding could open doors to connect myotonic dystrophy research with the ongoing work to restore dystrophin for Duchenne muscle dystrophy.

Therapeutic Development

As progress continues in the phase I/II clinical trial of antisense oligonucleotides for DM1, researchers are still developing alternative strategies to treat DM through a variety of different approaches.

Joel Chamberlain of the University of Washington demonstrated a gene therapy approach to neutralizing the toxic RNA that forms in muscle cells of mice that have a muscle symptom-causing expanded repeat inserted into their DNA. Dr. Chamberlain used a modified virus to act as a carrier for a small piece of genetic material designed to bind to the toxic RNA and trigger its destruction. The virus was able to enter the muscle cells of the mice and deliver the therapeutic genetic material, reducing the toxic RNA there by 60-95%. The treated mice showed a reduction in myotonia and less small muscle fibers than untreated mice.

MDF-funded Postdoctoral Fellow Suzanne Rzuczek of Scripps Research Institute has developed a particularly elegant way of using small molecules (chemicals) to inhibit the toxic RNA formed by DM1 expanded repeats. The challenge she faced was that these small molecules needed to form into large chains to be effective, but large chains were too big to get into cells easily. She solved the problem by designing small molecules that can enter the cell individually and then use the expanded repeat RNA itself as a scaffold for forming larger chains. The large chains then neutralized the activity of the expanded repeats. Small molecules can be easier to develop into drugs than therapeutics that use genetic material as their base and must be delivered via IV infusion.

Dr. Fan Zhang of Pfizer presented her efforts to screen for small molecules that can help alleviate the symptoms of DM1, not by neutralizing the toxic RNA formed by expanded repeats, but rather by increasing the amount of a key regulating protein called “MBNL” that is negatively affected by the toxic RNA. The loss of MBNL activity is thought to be the primary cause of many of the symptoms of DM1. Dr. Zhang created a modified version of the MBNL gene that causes cells to fluoresce green when MBNL is made. Using this system she was able to screen thousands of drugs from Pfizer drug libraries to identify compounds that can increase the amount of MBNL made. She has a few promising leads to date.

Work presented by Dr. Ralf Krahe of the University of Texas MD Anderson Cancer Center confirmed earlier observations that the strategy of neutralizing toxic RNA that is being employed as a therapeutic approach for DM1 may not be the best way to think about therapies for DM2. In DM1 the expanded repeat mutation occurs in a gene called “DMPK.” When the mutation was first discovered researchers wondered if the repeat was interfering with the function of DMPK and if all the symptoms of myotonic dystrophy were caused by the loss of this gene’s normal activity. Later work suggested that the loss of DMPK activity was unimportant and that the repeats by themselves were interfering with the function of many other genes - for example, when DMPK activity is eliminated in mice, the mice seem to carry on well without it. A strategy of neutralizing the toxic RNA formed by the repeat-containing DMPK gene has evolved. Unfortunately, it looks like the gene in which the expanded repeats occur in DM2, “CNBP,” is actually needed for normal function in mice. When this gene is “knocked out” in mice, the mice develop myotonia, myopathy and multi-system abnormalities. This means that strategies to neutralize toxic RNA in DM2 will need to be focused only on the copy of the gene that contains the expanded repeats, while the function of the normal gene will need to be preserved. Although technically trickier, investigators have been exploring ways to do this.

06/25/2015

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