Cognitive Decline Over Time

A new study just published shows more information on cognitive decline over Time in DM1. This study shows different results than many other studies. Isolating the issues to just a few areas. It seems a very comprehensive study with multiple patients and controls which strengthens the results. Also a number of cognitive tests were included.


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MDA awards $1 Million for Myotonic Dystrophy research

MDA Awards Nearly $1 Million to Continue Funding Myotonic Dystrophy Clinical Research Network

Investment will support five medical centers that specialize in DM research and clinical care

CHICAGO, January 24, 2017 – The Muscular Dystrophy Association announces the award of a clinical research network grant totaling $918,000 over three years to spur advances in myotonic dystrophy (DM) research.

Established in 2013, and supported by funding from MDA and other patient advocacy groups, the National Institutes of Health (NIH) and pharmaceutical company Biogen, the Network’s goals are to gain a more detailed understanding of the DM disease process and to collect data needed for clinical trials in order to inform what outcome measures, biomarkers and endpoints will be most appropriate.

“MDA is pleased to continue to enable this critical infrastructure for myotonic dystrophy research,” said MDA Scientific Program Officer Lianna Orlando, Ph.D. “Current and upcoming clinical trials in DM would not have been possible without MDA’s role in establishing the Network and supporting the creation of the tools necessary to carry out successful and informative studies.”

The Network currently is comprised of six medical centers with significant expertise in DM research and clinical care. Centers include:

  • California: Stanford University School of Medicine, Stanford
  • Florida: University of Florida College of Medicine, Gainesville
  • Kansas: University of Kansas Medical Center, Kansas City
  • New York: University of Rochester Medical Center, Rochester
  • Ohio: Ohio State University Medical Center, Columbus
  • Washington, D.C.: National Institutes of Health

MDA funds helped establish the Network’s original five university sites, and the new grant award continues to fund these programs. MDA funds do not support the NIH center. Additional sites may be added in 2017.

The Network is led by Charles Thornton, professor of neurology at the University of Rochester, who serves as its overall director.

“Now, for the first time, scientists and drug developers are coming up with good ideas about how to attack myotonic dystrophy at its root cause,” Thornton said. “The hope is that one of these new treatments will have a powerful effect, or that several can be used together.”

The Network was started, Thornton noted, to pave the way for testing new treatments in people.

“Experience has taught us that finding out whether a new drug is working or not is not a slam dunk. If we want to have clear answers, then we must work out many details and methods in advance,” Thornton continued. “And, we have to work closely with patients and families every step of the way. If it’s not a team effort, we probably won’t succeed.

“We are extremely grateful for support from MDA in getting the Network launched and keeping it going. When we started we hoped that we could encourage more companies and scientists to work on developing treatment for myotonic dystrophy, because they would see that all the tools are in place to conduct good clinical trials. Our work is still at an early stage but already we can see that this is happening.”

All of the researchers in the network have free and unrestricted access to data generated at all of the sites. In addition, and to further support advances in DM research, the Network is committed to making access to study results broadly available to both academic and industry researchers in the United States and around the world.

Among the Network’s accomplishments:

  • Network researchers have already been responsible for much critical clinical research in DM in the U.S., and through combined efforts they have standardized equipment and procedures (for measuring myotonic and muscle strength, and for obtaining blood and biopsy samples) across all sites.
  • The Network investigators published a DM biomarker study in December 2013 that looked at RNA splicing in muscle biopsy tissue and identified a group of gene splicing events that are affected even before there is evidence of muscle weakness. This collection of early changes in DM1 represent a tremendous opportunity for early/pre-symptomatic therapy intervention, and is being used as a potential biomarker to determine whether a treatment was effective at targeting the root cause of the disease process.
  • The five original Network centers are currently completing a multicenter observational study of type 1 DM in 100 individuals with the disease, while a companion study, conducted by the NIH site, is following 25 additional participants. The goals of both trials are to prospectively assess walking speed, muscle strength, muscle size, myotonia, heart rhythm, mental efficiency (attention, memory and cognitive tests), and overall health over a one-year period to determine how the condition changes over time.

MDA has funded more than $46 million in myotonic dystrophy research since 1950, and including this most recent award, is currently is funding nine active DM grants with a total funding commitment of more than $3 million.

The new grant was approved by MDA’s Board of Directors after careful deliberations and analysis by MDA advisors and research staff. This year, MDA is funding 150 different research projects in 11 countries.

About the Muscular Dystrophy Association
MDA is leading the fight to free individuals — and the families who love them — from the harm of muscular dystrophy, ALS and related muscle-debilitating diseases that take away physical strength, independence and life. We use our collective strength to help kids and adults live longer and grow stronger by finding research breakthroughs across diseases; caring for individuals from day one; and empowering families with services and support in hometowns across America. Learn how you can fund cures, find care and champion the cause at

Roxan Triolo Olivas
MDA Vice President Public Relations and Community Programs
(520) 529-5305

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New DM1 Myotonic Dstrophy Drug in Development

Audentes Therapeutics Expanding Treatment Candidates for Duchenne MD and Myotonic Dystrophy Type 1

Audentes Therapeutics Expanding Treatment Candidates for Duchenne MD and Myotonic Dystrophy Type 1

Audentes Therapeutics is expanding its pipeline of potential molecular therapies, expecting to address 80% of patients with Duchenne muscular dystrophy (DMD) and all with myotonic dystrophy type 1 (DM1).

The treatment strategy, called vectorized exon skipping, uses a modified adeno-associated virus (AAV) to deliver antisense oligonucleotides (ASOs) — small molecules complementary to the RNA sequence — to skip over mutated exons, the bits of DNA that contain the information to generate proteins. Such an approach leads to the production of functional and full-length proteins.

According to Audentes, this strategy may be superior in DMD to microdystrophin gene replacement approaches, which produce shorter-than-normal dystrophin — the protein missing in these patients — with potentially less durable clinical benefits. Also, it may be more beneficial than current ASO therapies, whose efficacy is limited by poor distribution in muscle tissue.

“Today’s announcement represents a significant step forward in expanding our scientific platform and deepening our pipeline of product candidates for neuromuscular diseases with high unmet medical need,” Matthew R. Patterson, Audentes chairman and CEO, said in a press release.

Patterson also said Audentes believes that this strategy, combined with the company’s large-scale current good manufacturing practice (CGMP) manufacturing capability, “can deliver best-in-class therapies for the treatment of [DMD] and [DM1].”

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To accelerate these programs, Audentes reached a licensing agreement and will partner with the Nationwide Children’s Hospital, as well as two of its experts on neuromuscular diseases — Kevin M. Flanigan, MD and Nicolas S. Wein, PhD.

“We are excited to be collaborating with Audentes to advance these novel, highly differentiated approaches for DMD and DM1,” said Flanigan, director of Nationwide Children’s Center for Gene Therapy.

Audentes and Nationwide Children’s are collaborating to develop AT702, a treatment candidate designed for skipping of exon 2 of the DMD gene — which codes for dystrophin — in patients with exon 2 duplications and mutations in exons 1-5.

In mouse models, AT702 led to dose-dependent increases in production of full-length or near-full-length dystrophin and improvements in muscle function. The company expects to start a Phase 1/2 trial of AT702 at Nationwide Children’s in the fourth quarter of 2019.

Audentes is also conducting preclinical studies of two other vectorized exon-skipping candidates known as AT751 and AT753. These investigational treatments are intended for DMD patients with genotypes amenable for skipping of exons 51 and 53. Both AT751 and AT753 use the same viral vector backbone as AT702, enabling a potentially quicker clinical development, the company says.

Overall, these three potential therapies target over 25% of patients with DMD, with the company planning to leverage its exon-skipping platform to cover up to 80% of DMD patients.

Besides DMD, Audentes and Nationwide Children’s are assessing vectorized RNA suppression and vectorized exon skipping for DM1.  Both strategies have been validated in studies with ASOs and intend to prevent the buildup of toxic RNA of the DMPK protein in cells, a hallmark of DM1.

The company is currently conducting preclinical studies and expects to file an investigational new drug application in the U.S. for its selected DM1 treatment candidate, AT466, in 2020.

Audentes’ current manufacturing capability enables global commercialization of AT132, a potential therapy for X-linked myotubular myopathy and the company’s lead program, as well as continued clinical development of its pipeline programs. The facility is designed for an eightfold expansion of its production capacity.

Audentes recently hosted a conference call and a webcast on the expansion of its AAV technology as well as the DMD and DM1 programs. A replay of the webcast and slides can be found here.

José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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The Journey of a Marathon Sleeper

A marathon sleeper who got away left some clues for Emory and University of Florida scientists to follow. What they found could provide benefits for patients with the genetic disease myotonic dystrophy (DM) and possibly the sleep disorder idiopathic hypersomnia (IH).

The classic symptom for DM is: someone has trouble releasing their grip on a doorknob. However, the disease does not only affect the muscles. Clinicians have recognized for years that DM can result in disabling daytime sleepiness and sometimes cognitive impairments. At the Myotonic Dystrophy Foundation meeting in September, a session was held gathering patient input on central nervous system (CNS) symptoms, so that future clinical trials could track those symptoms more rigorously.

Emory scientists are investigating this aspect of DM. Cell biology chair Gary Bassell was interested in the disease, because it’s a triplet repeat disorder, similar to fragile X syndrome, yet the CNS mechanisms and symptoms are very different. In DM, an expanded triplet or quadruplet repeat produces toxic RNA, which disrupts the process of RNA splicing, affecting multiple cell types and tissues.

Rye at San Francisco myotonic dystrophy meeting. Photo courtesy of Hypersomnia Foundation.

Neurologist and sleep specialist David Rye also has become involved. Recall Rye’s 2012 paper in Science Translational Medicine, which described a still-mysterious GABA-enhancing substance present in the spinal fluid of some super-sleepy patients. (GABA is a neurotransmitter important for regulating sleep.)

In seven of those patients, his team tested the “wake up” effects of flumazenil, conventionally used as an antidote to benzodiazepines. One of those patients was an Atlanta lawyer, whose recovery was later featured in the Wall Street Journal and on the Today Show. It turns out that another one of the seven, whose alertness increased in response to flumazenil, has DM.

In an overnight sleep exam, this man slept for 12 hours straight – the longest of the seven. But an IH diagnosis didn’t fit, because in the standard “take a nap five times” test, he didn’t doze off very quickly. He became frustrated with the stimulants he was given and sought treatment elsewhere, Rye says. Lab Land doesn’t have all the details of this patient’s history, but eventually he was diagnosed with DM, which clarified his situation.

More recently, Rye and his team have treated a small number (3) of DM patients with GABA antagonists — flumazenil or clarithromycin — with positive effects on alertness. Rye is collaborating with Andy Jenkins and Gary Bassell at Emory, and Eric Wang, a DM expert at the University of Florida.

Rye presented their findings both at the Myotonic Dystrophy Foundation meeting and at the World Sleep Congress in October. It appears that the RNA splicing perturbations in DM affect GABA receptors, and the GABA-enhancing substance is present too. That may produce a “double whammy” of sleepiness, according to Wang and Bassell.

Could scientists find hints to the identity of the GABA-enhancing “sleepy stuff” in IH by studying DM? Rye says:

“Additional basic science findings further suggest that there is much to be gained from examining hypersomnia through the lens of other disorders, especially one like myotonic dystrophy, whose genetics is well understood and where the field of scientists working on it is well developed. It’s a wonderful leveraging opportunity for two communities to inform one another.”

With the goal of treating more patients, Bassell, Jenkins, Wang and Rye are continuing this line of research, with the support of the Marigold Foundation. Jenkins – an expert on GABA receptors – has previously collaborated with Rye to study IH. The University of Florida has a cluster of DM expertise, including Laura Ranum, Andy Berglund and Maurice Swanson as well as Wang.

Bassell and his postdoc Anwesha Banerjee are collaborating with Rye and Wang to test the effects of GABA modulators in a nervous system-only mouse model of DM. Another strategy is to test antisense-style treatments – see below. Jenkins is examining the roots of the sensitivity of DM patients’ cells to anesthetics, a known problem leading to complications with anesthesia. Lab Land plans to learn more in the coming year.

Additional notes:

*While antisense-style drugs have been developed against SMA (spinal muscular atrophy) and DMD (Duchenne muscular dystrophy), Ionis Pharmaceuticals, which specializes in this type of drug, has reported setbacks in clinical trials aimed at treating muscle symptoms in myotonic dystrophy. The myotonic dystrophy community is actively working on the nervous system aspects for which no treatment is approved.At the MDF meeting (video here), several patients said they had tried modafinil.

*In human patients, the muscle weakness in DM can drive sleep apnea – so the sleepiness can be complex. Bassell’s nervous system-only mouse model could be helpful in dissecting the contributions of different tissues to sleep problems.

*Japanese and Polish scientists have observed that erythromycin, a chemical relative of clarithromycin, is effective in a DM mouse model, although the mechanism may be different and erythromycin is known to have cardiac side effects.

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Hypersomnia Foundation and Myotonic Dystrophy

Viewing Hypersomnias through the Lens of Myotonic Dystrophy

The improving the lives of people living with

  • Our DNA is the genetic code that our cells use to instruct them in how to make proteins, when and where to make them, and how much protein to make.
  • The code is contained in the specific order in which
  • Unrefreshing sleep despite long duration of their major sleep periods
  • DM1 has a known genetic cause, so it gives researchers a solid place from which to start unraveling the mystery of pervasive sleep in IH. Moreover, the key group of DM1 scientists is substantial, and animal models for DM1 exist. Therefore, this offers a wonderful leveraging opportunity for two disease communities to assist one another. And funding from the Marigold Foundation is making this opportunity a reality. In September 2017, Emory University (Drs. David Rye, Andrew Jenkins and Gary Bassell) and University of Florida (Drs. Eric Wang and Maurice Swanson) researchers began interdisciplinary, patient-centered, collaborative investigations of hypersomnia as seen through the lens of DM1. The knowledge to be gained promises to be substantial and directly relevant to the development of novel diagnostic approaches and treatments for idiopathic hypersomnia and related disorders.

    What Have We Learned So Far?

    In looking for biologies shared by IH and DM1 patients, researchers did not have to wander far. One node of commonality that was quickly appreciated was centered upon By Abigail Piccolo, BS, and David Rye, MD, PhD, Chairperson,

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