MDF is pleased to welcome Dr. Kathie Bishop, Ph.D., to its Scientific Advisory Committee(SAC). Dr. Bishop, who joined the SAC in summer 2015, is a seasoned expert in neurological and neuromuscular research and drug development.

She received her Ph.D. in neurosciences from the University of Alberta (Canada) in 1997 and then completed a postdoctoral fellowship in molecular neurobiology at the Salk Institute in La Jolla, Calif.

From 2001 to 2009, Dr. Bishop was at Ceregene, a San Diego biotechnology company developing gene therapies for neurological disorders. At Ceregene, where she was Director of Research and Development, she worked on preclinical and clinical programs in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, retinal degenerations, and amyotrophic lateral sclerosis (ALS).

In 2009, Dr. Bishop moved to Ionis (formerly Isis) Pharmaceuticals in Carlsbad, Calif., a biotech company specializing in antisense oligonucleotide-based therapeutics. While at Ionis, she led programs within the neurology franchise, including leading development for programs for spinal muscular atrophy, amyotrophic lateral sclerosis, type 1 myotonic dystrophy (DM1), and other rare genetic neurological disorders. She left Ionis Pharmaceuticals in 2015, as Vice President of Clinical Development.

She is now Chief Scientific Officer at Tioga Pharmaceuticals, a San Diego biotechnology company developing treatments for chronic pruritus. We talked with Dr. Bishop in October 2015:

MDF: What prompted your decision to move from academia to industry?

KB: I’ve always been interested in genetic neurologic diseases. My original degree was in genetics, and my Ph.D. is in neuroscience. While at the Salk Institute for my postdoctoral fellowship, I worked on development of the brain and spinal cord and found I wanted to apply the science to drug discovery and development.

MDF: What kinds of drug development programs have you worked on?

KB: At Ceregene, we were developing gene therapies for Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and ALS [amyotrophic lateral sclerosis].

When I moved to Ionis, my first program was developing antisense against SOD1 for ALS. We did a phase 1 clinical trial administering IONIS-SOD1Rx into the CSF [cerebrospinal fluid] in patients with the genetic form of ALS, and no safety issues were found. [See Miller et al., Lancet Neurology, May 2013.] At the time, we were concentrating on whether the CSF delivery of antisense drugs would be feasible and safe, which it was

I led the SMA [spinal muscular atrophy] program at Ionis from the preclinical stage through the phase 1 and phase 2 trials and up to trial design and initiation of phase 3 studies. IONIS-SMNRx acts on the SMN2 gene to change SMN2 splicing so that a functional protein is made. It acts right on the disease mechanism. This antisense [ASO] drug is the same chemistry as IONIS-SOD1Rx, but it doesn’t downregulate the SMN protein the way IONIS-SOD1Rx downregulates the SOD1 protein. The ASO doesn’t have a gap for an enzyme to bind that would downregulate the SMN RNA. It’s now in phase 3 studies in infants and in children with SMA.

I was also involved with developing IONIS-DMPKRx, an ASO against the DMPK RNA to treat type 1 myotonic dystrophy [DM1]. We completed a phase 1, single-dose study in healthy volunteers, and a multiple-dose study in adults with DM1 is ongoing. IONIS-DMPKRx destroys the DMPK RNA, which is thought to be the cause of DM1. It also affects the wild-type DMPK allele, but it may have a preference for the [abnormally expanded] DMPK RNA that’s stuck in the nucleus.

MDF: Do you see other therapeutic avenues for DM?

KB: Yes, absolutely. I think any one therapy, even one which acts on the genetic mechanism in DM, might not work perfectly in longstanding disease and might not work on all aspects of the disease or in all patients. We may need other compounds, such as muscle-enhancing drugs, to supplement it and be taken together with it. We will also need additional drugs that work on other aspects of DM, such as drugs that help stop degeneration in smooth muscle and heart, as well as CNS [central nervous system] drugs. Antisense drugs such as IONIS-DMPKRx do not penetrate into the CNS when given systemically, and particularly in the congenital and juvenile-onset forms of the disease, the CNS effects need treatment.

MDF: What do you see as the main challenges to drug development for DM and other rare disorders? For example, how can small companies meet the demands of patients for expanded access to compounds in development while pursuing full regulatory approval for these compounds?

KB: I think it’s the responsibility of people like me, who work in drug development, and of drug companies to communicate effectively about the development process and the risks involved to patients, their families, and their caregivers. We have to make it clear that experimental treatments could be harmful, and we have to be realistic and honest about the potential benefits. There is a lot of hope, but we also need to communicate better with the patient community about the drug development process.

That said, I would like to see the drug approval process be more efficient and go faster for diseases where the drug has a clear mechanism that acts directly on the underlying genetic cause of the disease. I think the FDA [U.S. Food and Drug Administration] is on board with this, but they aren’t going to come up with solutions. The drug developers have to do that.

MDF: What particular challenges do you see with drug development for DM?

KB: The clinical outcome measures used in this disease change very slowly, so you need long trials to measure decline. We need molecular markers, such as those reflecting splicing changes downstream of the mutant DMPK RNA that are linked to clinical changes. These are known as surrogate markers, and companies have to provide the data on these markers and clinical outcomes to the FDA.

MDF: What particular skills and insights will you bring to the MDF Scientific Advisory Committee?

KB: I plan to advise MDF on DM drug development and on incorporating science into drug development. I hope to help with encouraging and supporting new drug discovery and development programs for treatments for DM, advising on clinical trials, developing surrogate markers in DM, and having an effective working relationship with the FDA.

As part of our investment in the development of effective treatments for myotonic dystrophy, we are trying to better understand how people with DM weigh the benefits of new treatments against the risks.  To do this, we worked with a company called Silicon Valley Research Group to develop a survey that presented a series of hypothetical new treatments and asked that people choose the side-effects that concerned them the most and the least for.  This type of analysis is called “Max-Diff Analysis” or sometimes “Best-Worst Scaling” and has been used in other benefit-risk studies and by the Food and Drug Administration (FDA).  The method generates robust statistics to determine, on average, what risks people are or are not willing to accept for a given benefit.  The FDA has indicated that it is very interested in this type of information.  

The survey showed that reversing, stopping or slowing the progression of muscle weakness were the most preferred benefits, in that order.  The side effects people were most willing to tolerate overall for any benefit were loss of appetite and a small increase in tiredness. 

People in the study also completed the short version of the Myotonic Dystrophy Health Index (MDHI) to rate the severity of their myotonic dystrophy.  Scores were grouped into mild, moderate and severe categories.  For the majority of benefits, those with all levels of severity were similar in their willingness to tolerate side effects except that those with more severe myotonic dystrophy were less willing to risk liver failure for any type of therapeutic benefit.  Also, those with the highest severity rating for their myotonic dystrophy were more willing to tolerate an increase in tiredness if the drug could stop or reduce myotonia.  The data reported here are based on the survey responses from those with DM1.  The responses from those with DM2 are being analyzed now.

These results were presented on September 17th at the MDF-sponsored regulatory workshop on therapeutic development for myotonic dystrophy, which was attended by FDA staff.  Next steps will likely include an in-depth follow-on study that looks at the benefit-risk preferences of caregivers and younger people with myotonic dystrophy.  We are also investigating ways to collect “qualitative” data, such as stories and open-ended comments, on the benefit-risk preferences of those with myotonic dystrophy.  Ultimately this information will be made available to FDA reviewers through various mechanisms with the goal of incorporating the view of those with myotonic dystrophy and their families into the decision-making process about new therapies. 

Providing care to the very young, the very old, and to children and adults with illnesses or disabilities has always been part of family life and is highly likely to remain so, in the United States and elsewhere. But the last 50 years have been a time of marked changes in the U.S. and other developed countries in the circumstances families face when they need to provide care to dependent relatives.

Family Caregiving Has Changed

Women, even those with young children, are far more likely to be in the paid workforce than ever before; families often do not live near relatives who in the past might have provided support; elderly relatives are surviving longer than in earlier decades but more often have multiple, age-related care requirements; and children who in the past did not survive infancy are living through childhood and even adulthood, sometimes with serious deficits and complex needs.

Outside Resources Are Scarce

Government and other support for care in the home vary greatly among countries, with the U.S. providing relatively little in terms of a safety net compared with many western European nations. (In the U.S., the Family and Medical Leave Act requires that some businesses and other employers allow 12 weeks of unpaid leave with job protection for employees who want to care for an ill family member or a new baby.)

Caregivers Experience an Array of Challenges

In June 2015, the National Alliance for Caregiving and the American Association of Retired Citizens (AARP) released a report – Caregiving in the U.S. – that showcases some of the challenges facing today’s family caregivers.

The report is based on interviews conducted in 2014 with 1,248 caregivers who were at least 18 years old and were providing unpaid care to at least one adult or child in need of special attention. (Parents of children requiring “ordinary” care – without special needs – were not part of this survey.) Among the findings were the ollowing.

One in eight Americans is a caregiver, usually for a relative:

• There are an estimated 43.5 million adults in the U.S. (or one in every eight Americans) providing care to at least one adult or child with special needs, on average providing 24.4 hours a week of care.
• Most caregivers – 60 percent – are female; 40 percent are male.
• The average caregiver age is 49.
• A large majority of caregivers – 85 percent – are providing care for a relative.

Most caregivers also have a full-time job:

• More than half (56 percent) of caregivers in this survey were employed in a full-time job in addition to their caregiving responsibilities; on average, they worked 34.7 hours a week.
• More than half (60 percent) of those surveyed said they had to make workplace accommodations, such as reducing their hours or taking a leave of absence, because of their caregiving role.

A third report no help:

• About a third (32 percent) of caregivers report they are assisted by paid help, such as an aide.
• One in three (33 percent) report they have no help at all.
• About a quarter (24 percent) of caregivers reported difficulty obtaining affordable services that would help with their caregiving in their community.
• Of caregivers providing at least 21 hours of care per week, 44 percent said respite care (with someone else taking over the caregiving for a defined period of time) would be helpful.

40 percent say burden of care is high:

• Most caregivers – 59 percent – help loved ones with at least one activity of daily living (ADL), such as helping them get in and out of beds and chairs and assisting them with bathing or showering.
• One in four caregivers (25 percent) reported assisting with ADLs was difficult.
• The most difficult ADLs with which caregivers assist involve personal care, such as dealing with diapers or incontinence (40 percent said this was difficult); helping the care recipient to and from the toilet (33 percent said this was difficult); and helping with bathing and showering (31 percent said this was difficult).
• Other caregiver responsibilities reported by those interviewed included transportation, shopping, housework, managing household finances, interacting with healthcare providers and other professionals on the care recipient’s behalf, and performing medical or nursing tasks, such as giving injections or tube feedings and providing catheter or colostomy care.
• About a quarter (22 percent) of caregivers said their own health had worsened as a result of their caregiving responsibilities.
• A high level of physical strain related to caregiving was reported by 19 percent of caregivers; 38 percent considered caregiving to be emotionally stressful.
• Financial strain resulting from caregiving was reported by 18 percent of caregivers.
• The burden of care perceived by caregivers was reported as “high” by 40 percent of survey responders, “moderate” by 18 percent, and “low” by 41 percent.

Caregiving in a DM-Affected Family Often Means Meeting Diverse Needs

MDF dystrophy (DM), particularly the type 1 form, poses specific caregiving challenges to families, as the disease affects the muscles, brain and many other organs and systems in the body.

There is often more than one person affected in a DM family – and they aren’t all affected in the same way. It isn’t at all unusual to find a middle-aged, unaffected adult caring for a spouse with adult-onset DM1, a son or daughter with juvenile-onset DM1, and a grandchild with congenital DM1.

A DM1-affected spouse may be experiencing weakness and fatigue, while the juvenile-onset-affected adult may be finding school or work unsustainable because of cognitive impairment and daytime sleepiness; and the baby in the family, with congenital DM, may require specialized care, such as respiratory treatments and tube feedings, as well as many hours a week of therapies to aid his or her cognitive and physical development.

Voices of Caregivers in DM Families

In the U.S., caregivers in DM families who have been profiled on the MDF website and who facilitate online support groups for caregivers report a combination of challenges and satisfactions with their roles, which often involve caring for spouses and children with the disease.

Diane Bade, a middle-aged caregiver of three children with DM, says her children “live vicariously through others” and that their “social networks and outlets are limited by their circumstances.” To help offset those barriers, she started an annual sleepover camp for young adults with DM at her home.

Cecilia Stearns describes having an adult daughter whose social problems, daytime sleepiness and learning disabilities, which started in her teens, weren’t recognized as DM1 until Danielle herself experienced serious complications during childbirth and gave birth to twin boys with congenital DM. “You just do what you have to do,” Cecilia says. “We’re all here and doing as well as we can. The typical retirement does not exist for us, but we’ve got our daughter and two 15-year-olds who need us. I can’t imagine my life without them.”

Regina Thompson describes caring for her adult, DM1-affected brothers: “It was perfectly normal that we’d stick together and take care of each other,” she says. “I always wanted to take care of my brothers as best I could. What I’ve learned at the MDF Annual Conferences and through other resources helps me take care of them. We’ve been dealt things we have to live with, but your perspective really can make all the difference.”

Kevin Dressler, featured in "Reaping the Rewards of an Unexpected Role", whose wife, stepdaughter and step-grandchild all have DM1, is going to be participating in an online support group for male, unaffected caregivers in DM families, the outgrowth of a community-led panel he helped lead at the 2015 MDF Annual Conference. He advises men in his situation to be patient and accept that you can’t run away but that you are not alone and can reach out to friends and support groups. Kevin’s grandchild, now 3 years old, is “blossoming” despite having congenital DM, and getting a hug from the little boy at the end of a work day offsets the difficulty of caregiving.

Even Overseas, Things Aren’t Perfect

Even in the Netherlands, where the government provides more social services for caregivers than it does in the U.S., a study published in 2014 found parents of children with a chronic illness worked fewer hours per week (if voluntary, this could be viewed as a benefit) and spent less time doing leisure activities than parents of healthy children. The researchers surveyed 576 parents of ill children and 441 parents of healthy children.

In another Dutch study, published in 2011, researchers looked at five middle-aged couples in which one person was affected by adult-onset DM1. They conducted in-depth interviews with the couples, separately and together, in two cities and three villages in the Netherlands in 2009.

They found that the partners with DM1 experienced physical, cognitive and psychosocial barriers to performing roles and participating in activities in life, leading to postponing, avoiding, adapting or giving up activities. The unaffected partners reported experiencing increasing burdens, feeling they had to do everything, including prompting their affected partners to act. In addition, couples described a lack of understanding of the DM-affected person’s condition by relatives and friends, the healthcare system and society in general. They described the healthcare system in the Netherlands as fragmented and uncoordinated, with each set of professionals looking at one aspect of DM1 at a time and no one putting the whole picture together or understanding the impact of the disease on daily life.

Resources for Caregivers

Supporting caregivers and families is one of the most important things we do. Visit the links below to explore some of the caregiver resources available on the MDF website. If you don’t find what you need, contact MDF, we’re here to help.

Join us, November 23rd, for a Meditation for Caregivers - a virtual, hour-long session with Dr. Genie Palmer, a meditation teacher and former associate professor and researcher at Sofia University. 

MDF Caregivers Support Group (notices about upcoming discussions, held online every month)

MDF Caregivers Group (a Facebook-based group)

MDF Unaffected Male Caregivers Group (a Facebook-based group)

2014 MDF Annual Conference Community-Led Track: Caregiver Focus (a 45-minute presentation discussing challenges facing caregivers)

2014 MDF Annual Conference: Advocating in the Clinic – Educating & Supporting Your Doctors (a 54-minute presentation on becoming your own healthcare advocate and educating your doctors about your needs)

Webinar: On Being a Fearless Caregiver (a 43-minute presentation on issues related to caregiver advocacy; partnering with the healthcare team and other family members; self-care; and managing the role of a caregiver)

Antisense Oligonucleotides and DM1

Targeting antisense oligonucleotides (ASOs) to expanded CUG repeats has received increasing interest as a means to suppress the RNA-mediated toxicity that is mechanistic in DM1. While the strategy initially focused on using ASOs to sterically block the binding of MBNL protein to structural hairpins formed by the expanded triplet repeats in DMPK (Wheeler et al., 2009), there appears to now be a consensus toward instead triggering RNase H-mediated degradation of the toxic RNA (Lee et al., 2012; Wheeler et al., 2012). Clinical trials based upon this strategy (IONIS-DMPK-2.5 Rx) did not achieve adequate bioavailability at the skeletal muscle target, but there appear to be multiple alternatives to correct this delivery problem. Strategies range from further optimizing ASO backbone chemistry to conjugation with any of a variety of agents capable of mediating translocation across the sarcolemma.

Evolving a Promising Strategy

Penetration of ASO drugs into muscle fibers for exon skipping in Duchenne muscular dystrophy is thought to be mediated, at least in part, by the frank sarcolemmal breaks present in this disease. Sarcolemmal disruption, however, is not a component of the pathogenesis of DM1. Linking large molecule drugs, such as ASOs, to cell-penetrating peptides represents one strategy to augment the often slow and limited transition of these drugs across an intact sarcolemma. A new paper in Journal of Clinical Investigation from Drs. Matthew Wood (Oxford University) and Denis Furling (Institute of Myology) and their colleagues explore the potential of an arginine-rich Pip6a cell-penetrating peptide to enhance bioavailability and efficacy of PMO-based ASOs in a mouse model of DM1 (Klein et al., 2019).

Low dose treatment of mice with the Pip6a-PMO-CAG conjugate proved superior to both naked PMO and other previously published ASO chemistries in reversing mis-splicing defects and myotonia in HSA^LR mice. Systemically delivered Pip6a-PMO-CAG (2-3 iv injections at 12.5 mg/kg each) produced complete splice correction of three test transcripts, reduced expanded repeat RNA and nuclear foci, and abolished myotonia. Splicing correction duration was reported as extending as long as six months.

Efficacy with the Pip6a conjugate tested here was achieved at doses 5-10x less than those reported in previous publications with other ASO formulations. Transcriptome analysis further established that broad splicing correction was obtained. These findings contrasted with little or no effect obtained with naked PMO. The research team also demonstrated biodistribution to cardiac muscle.

Finally, the research team showed that the Pip6a-PMO-CAG conjugate displaced MBNL from nuclear foci, reduced toxic RNA levels, and corrected splicing in four test transcripts in treated DM1 patient muscle cell cultures with large expansions (2600 and >1300 repeats). Again, effects were superior to naked PMO.

Going Forward

The authors have tested one candidate cell-penetrating peptide as a delivery vehicle for ASOs based upon an RNase H strategy to mitigate DM1. While efforts to select the optimal cell-penetrating peptide are still warranted (since no head-to-head tests of alternative peptides were done here), these data provide additional proof of principle that enhanced delivery may help overcome the hurdles encountered in DM1 clinical trials to date. Taken together, these findings support the renewed efforts to improve the delivery of ASOs to DM1 patient skeletal muscle and thereby address what is most likely the primary barrier to the efficacy of this therapeutic strategy.

References:

Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA.
Wheeler TM, Sobczak K, Lueck JD, Osborne RJ, Lin X, Dirksen RT, Thornton CA.
Science. 2009 Jul 17;325(5938):336-9. doi: 10.1126/science.1173110.

RNase H-mediated degradation of toxic RNA in myotonic dystrophy type 1.
Lee JE, Bennett CF, Cooper TA.
Proc Natl Acad Sci U S A. 2012 Mar 13;109(11):4221-6. doi: 10.1073/pnas.1117019109. Epub 2012 Feb 27.

Targeting nuclear RNA for in vivo correction of myotonic dystrophy.
Wheeler TM, Leger AJ, Pandey SK, MacLeod AR, Nakamori M, Cheng SH, Wentworth BM, Bennett CF, Thornton CA.
Nature. 2012 Aug 2;488(7409):111-5. doi: 10.1038/nature11362.

Peptide-conjugated oligonucleotides evoke long-lasting myotonic dystrophy correction in patient-derived cells and mice.
Klein AF, Varela MA, Arandel L, Holland A, Naouar N, Arzumanov A, Seoane D, Revillod L, Bassez G, Ferry A, Jauvin D, Gourdon G, Puymirat J, Gait MJ, Furling D, Wood MJA.
J Clin Invest. 2019 Sep 3. pii: 128205. doi: 10.1172/JCI128205. [Epub ahead of print]

Researchers at the University of Virginia recently published a paper describing a biological pathway they believe is affected in people with myotonic dystrophy (DM). Previous studies have identified the DNA mutations causing both types of DM, and determined that the RNA molecule made from the DNA is the culprit in causing toxicity in the cell and leading to symptoms of DM.

Though DM symptoms such as myotonia have been linked to the toxic RNA molecule, other symptoms such as muscle weakness and muscle wasting have not been fully explained. This study identifies a possible pathway, the TWEAK/Fn14 pathway, which appears to be activated in DM mouse models and in muscles of people with DM1. The authors suggest this pathway may be responsible for muscle degeneration in DM1, and that blocking the pathway might prove beneficial. A drug blocking this pathway, known as the anti-TWEAK antibody, is currently in trials for other diseases.

When the anti-TWEAK antibody was tested on a very small sample of DM mouse models, there were improvements in muscle appearance and function. However, the treatment was not sufficient to reverse myotonia or cardiac conduction defects in the mouse models. The authors concluded that the treatment will likely not cure myotonic dystrophy, but instead may be better suited for a therapeutic approach involving a combination of experimental treatments.

Further analysis is necessary to determine whether the TWEAK/Fn14 pathway and targeting it in individuals with DM1 provides a worthwhile therapeutic strategy. The pharmaceutical company Biogen Idec and the Mahadevan Lab at the University of Virginia have been conducting an investigative collaboration for several years studying the pathway and the anti-TWEAK molecule. Anti-TWEAK may be used at some point in the future to target specific diseases that may or may not include DM, but plans and dates have not been formulated. MDF will keep the community apprised if developments become available.

05/21/2015

Modifying the DNA of DM Stem Cells to Treat Symptoms

Researchers at the University of Florida, led by Dr. Tetsuo Ashizawa, recently published a study in which they developed a strategy for DM1 stem cell therapy involving gene modification. This proof-of-concept study demonstrated that the genetic approach designed by the Ashizawa lab could be effective in reversing cellular defects that cause DM symptoms. Someday successful gene modification could be used to enable personalized stem cell therapy, in which cells are obtained from a person with DM1, treated to address the gene mutation, and transplanted back into the patient with the hope of restoring normal tissue function and treating symptoms.

Dr. Ashizawa's lab used cells obtained from skin biopsies of people with DM1. The cells were converted to stem cells called induced pluripotent stem cells (iPSCs) that can produce cells for every tissue in the body. The stem cells were then converted to develop brain cells. Following this conversion, the DMPK gene in the brain cells was targeted to reverse negative effects of the DM1 mutation that causes disease symptoms. This strategy proved to be effective, as the lab successfully genetically modified the brain cells, and restored normal cell function.

Despite the positive study results, limitations and challenges exist that must be addressed before this approach can be used to treat people with DM1. First, additional research must demonstrate that this genetic approach is safe as a treatment. Genetic modification of cells can result in unexpected side effects, such as unwanted mutations elsewhere in the gene. Secondly, the modification to the DMPK gene may have negative effects on normal gene function, and we need to explore this possibility. In addition, we need to improve the transfer of modified stem cells into brain, muscle, and heart tissue in order to get the best possible impact on disease symptoms.

While Dr. Ashizawa's team and others are conducting studies to address these challenges, this study is an exciting first step in efforts to build a stem cell therapy for DM1 and move gene therapy for DM1 to the clinic.

Read the abstract of this study.

04/23/2015

February is American Heart Month, and MDF has partnered with Drs. Katharine Hagerman and Marianne Goodwin to highlight important research on cardiac issues in myotonic dystrophy for our community.

Researchers in the lab of William Groh, MD, at Indiana University have been studying heart involvement in myotonic dystrophy type 1 (DM1), including heart conduction defects, cardiac rhythm disturbances, and structural heart abnormalities for some time. The group performed cardiac imaging and analysis of the electrical impulses of the heart by electrocardiography (ECG or EKG) on individuals with DM1, and found that certain structural changes in the heart are increased in individuals with cardiac electrical abnormalities. In addition, the study identified predictors of heart failure and dysfunction, including increased age and changes in electrical conduction of the heart observed by ECG, specifically measurements known as PR interval and QRS duration. These indicators may be used by doctors to help predict which DM patients would benefit most from implantable cardiac rhythm devices such as pacemakers. Additionally, the group found that some individuals with DM1 benefit more from devices known as implantable cardioverter-defibrillators (ICDs) than standard pacemakers to help correct heart rhythm disturbances.

The heart involvement in myotonic dystrophy type 2 (DM2) is similar to that seen in DM1, however controversy exists over the frequency and severity of heart irregularities in the DM2 population. To address this, a research team led by Giovanni Meola, MD, in the Neuromuscular Clinic at IRCCS Policlinico San Donato in Italy compared cardiac abnormalities in DM1 and DM2. Using tests such as ECG and echocardiography, the study found that heart involvement is less common and generally milder in DM2 than DM1. However, individuals with DM1 and DM2 are both at increased risk of heart abnormalities such as cardiac arrhythmias and conduction disturbances. These heart irregularities can be progressive with age, and may be present in individuals even when no symptoms are experienced. Therefore, people living with DM should receive annual cardiac evaluations, including ECG, by primary care physicians or cardiologists to promote heart health.

For more information on heart health in DM, please see our Body Systems Tool.

To learn more about heart symptoms, exams and management, watch MDF's webinar "Cardiac Issues Related to DM," by Dr. William Groh, a leader in the field.

Papers on DM1 heart issues:

• "Pacemaker and Implantable Cardioverter-Defibrillator Use in a US Myotonic Dystrophy Type 1 Population"
• "Prevalence of Structural Cardiac Abnormalities in Patients with Myotonic Dystrophy Type 1"
• "Increased Mortality with Left Ventricular Systolic Dysfunction and Heart Failure in Adults with Myotonic Dystrophy Type 1"

Papers on DM2 heart issues:

• "The Frequency and Severity of Cardiac Involvement in DM2: Long-term Outcomes"

02/26/2015

Tackling DM from Basic Research through Clinical Care

Tetsuo Ashizawa, MD, better known as "Tee" to colleagues and patients, has focused his career on the search for treatments for myotonic dystrophy (DM). As one of seven primary investigators who will participate in the first clinical trial of a potential treatment for DM1, Dr. Ashizawa may be closer than ever to achieving that goal. Yet in addition to pursuing research with dedication and tenacity, he has also been committed to providing the best possible care to people living with DM. Dr. Ashizawa's engagement in myotonic dystrophy spans basic research, translational science, patient-oriented research and clinical care.

Originally trained in neuromuscular diseases, Dr. Ashizawa first became involved in DM as a basic researcher, working with a team at Baylor College of Medicine to hunt for the DM gene. "There were actually several teams working internationally to find the gene," said Dr. Ashizawa. "Interestingly, in 1992 the various research teams all had the same finding, which was identification of DMPK, the genetic mutation responsible for myotonic dystrophy type 1. It was an exciting time, and that was the beginning of our journey to find treatments and a cure."

Patients Play a Key Role with Researchers

In 1998, as Dr. Ashizawa was expanding his research efforts, he received an email that would broaden his perspective. Shannon Lord, the mother of two boys with juvenile-onset DM1, wanted to make a donation to advance DM research. She provided a grant to Dr. Ashizawa through the Hunter Fund, an account named after her older son and established by Shannon and her husband Larry to support DM research projects. The grant was the start of a long-term friendship between Dr. Ashizawa, Shannon and Larry Lord, and ultimately led to a DM scientific meeting organized by Dr. Ashizawa and including the Lord family. "It was so powerful," said Dr. Ashizawa. "Before this meeting, many in the scientific community only saw DM through a microscope. Now investigators could see and understand the human face of the disease. It was a real morale booster for everyone and provided a great deal of momentum to move our work forward."

By then Dr. Ashizawa had also co-founded the International Myotonic Dystrophy Consortium (IDMC) to bring together scientists and clinicians focusing on DM. Shannon Lord attended the third biennial IDMC meeting in Kyoto in 2001, serving in the role of patient advocate and introducing patient advocacy to the IDMC research community. By the fourth meeting, about one hundred patients and families attended, and the participation of a large number of patients at these international meetings has since become routine. Today, IDMC meetings provide a unique opportunity for global researchers, clinicians and patients to come together; IDMC 10 will be held next June in Paris, France. "Without patient involvement, we wouldn't be able to push forward on the research frontier," Dr. Ashizawa said.

Research Moves Out of the Lab

By 2011, DM science had progressed significantly in the development of potential treatments for DM1. Seven research and clinical institutions around the country are currently preparing to launch the first clinical trial in affected patients to test the efficacy of an antisense oligonucleotide (ASO) therapy, DMPKrx, in people affected by DM1. The University of Florida (UF) will serve as one of these sites, with Dr. Ashizawa as the Primary Investigator for the institution.

Dr. Ashizawa has recently started a project looking at DM1 patient-derived, induced pluripotent stem cells (iPSCs), which can be developed into different cell types needed for research, e.g. muscle, heart, or even brain cells. These cells can help researchers understand how DM affects different body systems and causes disease symptoms. While the clinical use of these cells may be a long way off, iPSCs have a more immediate and critical function as a platform for the screening of compounds to find drugs that have therapeutic potential in DM1. "It's a very exciting time in DM research," Dr. Ashizawa says.

Providing Multidisciplinary Care in the Clinic

In addition to his research projects, Dr. Ashizawa oversees the clinical program at the University of Florida. Patients benefit from a multidisciplinary team of doctors that includes cardiologists, anesthesiologists and geneticists. "We help patients access any clinical trials for which they may be eligible," he says. "And when new treatments become available we are committed to helping our patients access them as soon as possible."

Dr. Ashizawa has published over 190 research papers and 35 book chapters. He is currently Executive Director at the McKnight Brain Institute at UF and Professor and Chair of the Department of Neurology at the UF College of Medicine, and he serves on MDF's Scientific Advisory Committee. With Drs. Maurice Swanson and S.H. Subramony, he has recruited Dr. Laura Ranum to UF and is in the process of recruiting a handful of other key DM investigators to build one of the strongest DM research teams in the world. "We are very hopeful about the research and treatment possibilities on the horizon. We have a distance to go and there are many questions to answer, but we won't stop working," says Dr. Ashizawa. "We are dedicated to our patients and to collaborating with them to find a cure."

12/09/2014

Dahlqvist et al
European Journal of Neurology

Dr. John Vissing and his colleagues at the University of Copenhagen recently tracked a group of 68 adults with myotonic dystrophy type 1 (DM1), measuring their endocrine function change over 8 years.  The authors examined bloodwork for many endocrine dysfunctions including diabetes (HbA1c blood test), hyperparathyroidism (PTH blood test), and androgen insufficiency (testosterone blood test in men), and found that these dysfunctions became more common over time in people with DM1.  The authors recommend that doctors treating people with DM1 should screen for endocrine functions regularly, as the dysfunctions occurs more frequently in DM1 than the general population.

Click here to read the abstract for this study.

Click here for a PDF of this paper.

10/16/2014

Dr. Katharine Hagerman, Research Associate at Stanford University Neuromuscular Division and Clinics, has prepared the following summary of the recently published study, "Parental Age Effects, But No Evidence for an Intrauterine Effect in the Transmission of Myotonic Dystrophy Type 1" in the Journal of Human Genetics. 

Researchers from the laboratories of Fernando Morales from the University of Costa Rica, and Darren Monckton from the University of Glasgow collaborated in a recent study examining how the DNA mutation causing myotonic dystrophy type 1 (DM1) worsens from one generation to the next. Previous studies have shown that the DM1 mutation behaves differently depending on whether it is passed on from the father or mother. However, there has been conflicting information regarding whether the age of the parent’s symptom onset or parent’s age at conception of their affected child can change the degree to which the child is affected by DM1.

The conflict in research findings is likely the result of using different methods to assess the size of the DM1 mutation, and failing to account for the age of the parent at the time the blood was collected, since the mutation grows throughout their lifetime. This study uses a newer technique called "small pool PCR" to assess the mutation size, and a complex statistical analysis to predict what the original size of the repeat was at birth. This method clarified the relationship between parent and child with regard to CTG repeat size and symptom onset, confirming that children born with DM1 have an inherited repeat that is larger than their parent’s repeat about 95% of the time, and symptom onset comes earlier in the child than their affected parent around 86% of the time. Furthermore, the parent’s age of onset is correlated with the child’s age of onset, but the correlation is much stronger in affected mothers than fathers.

What really stood out in this paper was a completely new finding that the age of the affected parent at conception correlates with the repeat size in their child. In other words, as people with DM1 age, the size of the repeat in their eggs or sperm grows larger. Basic genetic principles dictate that there is a 50% chance of an affected parent passing on the mutation to their child.

This paper found that if the child inherits the mutation from their mother and gets DM1, there is a 64% risk of the child’s DM1 being congenital if the mother’s repeat size is above 164 CTGs. There are very few cases of an affected father having a congenitally affected child, and none were found in this study. Unfortunately, current procedures for diagnosing DM1 do not use the same experimental method as in this paper and do not predict what the individual’s repeat was at birth. Therefore this predicted risk cannot be applied to mothers whose repeat was sized using conventional methods for diagnosis.

The authors estimate that the diagnostic test most women get to determine the size of their repeat would also predict that if their offspring inherit the expanded repeat, they would be congenitally affected 64% of the time when the mother's repeat length is over 284 CTGs.

Genetic counseling for families with DM1 can be very complicated, as many factors such as the repeat size and sex of the DM1-affected parent can alter any predictions as to how severely a child may be affected. Overall, this study clarifies how the growing repeat size in adults with DM1 can affect their children, and brings to light a new factor to be considered by genetic counselors when advising families of the risks of transmitting DM1.

Click here to view the article abstract. Click here for an interview on genetic counseling with Carly Siskind of Stanford University Hospital and Clinics.

08/20/2014