The Muscular Dystrophy Association has awarded 33 new grants totaling $10,684,481 to fund research projects focused on uncovering the causes of, and developing therapies for, neuromuscular disease.

MDA's Board of Directors reviewed and approved the new grants based on recommendations from the Association's Scientific and Medical Advisory Committees, and the grants took effect Aug. 1.

The new grants support the search for causative genetic defects, altered biological processes and pathways, and development and refinement of therapeutic strategies for nearly half of the more than 40 diseases in MDA's research program. Although a number of the projects focus on a single disease, results will have implications for many diseases of muscle and nerve.

To learn more about any of these grants, see the Grants at a Glance slideshow.

Multiple diseases covered

Of the 33 new awards, 29 are research grants meant to support projects designed to answer specific questions about one or more neuromuscular disease. Four grants are development grants, which are designed to increase the number of outstanding scientists working on neuromuscular disease by supporting their research at a critical stage in their careers.

The grants support studies in cell therapies, and general muscle health and function, as well as research into 18 neuromuscular diseases in MDA's program.

Some researchers have goals aimed at a particular disease, or a group of diseases, but all the grants help inform general muscle research and move muscle disease research forward.

Specific topics, multiple hits

In several instances, the grants fund research projects that get at the same topic from different angles.

For example, three new grants are for research focused on the search for specific gene defects that cause some rare forms of congenital muscular dystrophy (CMD), Charcot-Marie-Tooth disease (CMT) and facioscapulohumeral muscular dystrophy (FSHD). Any genes identified may provide targets at which to aim therapies.

Several grants involve the use of autologous adult stem cells for therapies aimed at muscle repair and regeneration. Such cells are derived from a person's own body — for example, from the skin, fat or bone marrow — and coaxed into becoming muscle cells or other desired cell types, then returned to the same person from whom they were taken. Cell-based therapies involving the transplantation of a person's own stem cells instead of cells taken from another source have a greater chance at success, as they are far less likely to trigger an immune system response that could make the body reject the new cells.

A number of grants also are focused on nonmuscle problems in neuromuscular diseases. For example, in Duchenne and Becker muscular dystrophies, researchers are characterizing the details of cognitive and behavioral problems, and also examining the role in fatigue of abnormal regulation of blood flow by nitric oxide.

Disease-specific grants

In acid maltase deficiency (AMD, or Pompe disease)  research, scientists will work on development of a drug that helps gene therapy work better.

Cellular stress responses and nongenetic risk factors are being investigated in amyotrophic lateral sclerosis (ALS) research. (See ALS: New MDA Grants Focus on Multisystem Aspects of the Disease.)

Scientists working on Charcot-Marie-Tooth disease (CMT) will study how defective Schwann cells cause nerve damage; the role of proteins called lamins in normal and diseased muscle; the effects of damage to the cellular-energy producing mitochondria; and genes that cause CMT.

Researchers studying congenital muscular dystrophy (CMD) will be looking at normal and abnormal muscle development; the creation of research models; mechanisms underlying the CMD disease process; and genes that, when mutated, cause CMD.

Researchers who study congenital myasthenic syndromes (CMS) will be working to determine the underlying mechanisms of movement disorders in the disease.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) researchers will be studying "membrane sealant" therapies; stem cell strategies; the role of the gamma-actin protein in muscle degeneration and weakness; the therapeutic potential of a protein called laminin-111 and another called myostatin; how the system of blood vessels known as vasculature affects muscles; genetic correction and muscle regeneration; mechanisms underlying muscle fatigue; and cognitive problems in children with DMD.

In Emery-Dreifuss muscular dystrophy (EDMD), researchers will be looking at LMNA gene mutations and the role of a protein called ensconsin in the disease.

New projects infacioscapulohumeral muscular dystrophy (FSHD) include creating a better mouse model of FSHD; a therapeutic approach based on a strategy called RNA interference; development of a new FSH mouse research model; and the identification of genetic elements that can influence FSHD disease onset.

Investigators will be studying how Schwann cells cause nerve damage (neuropathy) in Friedreich's ataxia. 

Research in limb-girdle muscular dystrophy (LGMD) will focus on the role of proteins called lamins in both healthy and diseased muscle; the identification of genes that, when mutated, can cause LGMD; the underlying mechanisms of muscle weakness and fatigue; and an enzyme called calpain 3.

"Molecular bypass therapy" will be the focus of research in a mitochondrial myopathy called thymidine kinase 2 (TK2) deficiency.

Scientists working in myasthenia gravis (MG) will be focusing on a potential cell-based therapy involving immune system B cells, and the role of a protein called LRP4 in the disease.

In myotonic muscular dystrophy (MMD or DM), scientists will be working to determine why progressive muscle degeneration occurs, and to identify therapeutic agents that slow the progression of muscle degeneration or otherwise improve muscle health.

An understanding of genetic causes and disease process will be studied by scientists working on nemaline myopathy (NM).

In spinal-bulbar muscular atrophy (SBMA), investigators will be studying a new therapy approach aimed at promoting degradation of the androgen receptor (AR) protein by stabilizing another protein called heat shock protein 70 (Hsp70).

Researchers also will be investigating similarities between CMD, LGMD, BMD/DMD, MTM, NM and collagen disorders.

Supporting new researchers

Four career development grants are included in the 33 new grants. Recipients of this type of grant work in the laboratory of a senior investigator, where each is given the flexibility to work independently or as part of a collaborative effort.

• Bogdan Beirowski at Washington University in St. Louis is focused on determining how nervous system support cells called Schwann cells lead to nerve-cell damage in CMT.
• Tathagata Chaudhuri at the University of Pennsylvania in Philadelphia is working on development of a stem cell therapy for muscular dystrophies, including DMD and BMD.
• David Gokhin at the Scripps Research Institute in La Jolla, Calif., is studying the connection of a protein called gamma-actin to muscle degeneration and weakness in DMD and BMD.
• Ryan Wuebbles at the University of Nevada School of Medicine in Reno is studying the potential of a protein called laminin-111 as the basis of therapies for DMD and BMD.

Learn more

For up-to-date information on all the latest MDA-funded research projects see Grants at a Glance, a slideshow feature with photos and information on the new MDA grantees and their research, and ALS: New MDA Grants Focus on Multisystem Aspects of the Disease.

To review the approximately 300 active research grants currently being funded by MDA, view this PDF.

As an energetic youngster in Menlo Park, Calif., Joe Wise’s favorite sports were baseball and football. Once he developed allergies and asthma, though, his mom, Marie, insisted that he add swimming to his athletic pursuits to improve his health.

When Wise turned 9, his parents noticed alarming changes — he moved slower and complained of hip pain. His legs became weaker and writing was difficult. That year, doctors diagnosed him with mitochondrial myopathy. There was a good chance, they said, that he wouldn’t live to see his 15th birthday.

But Wise had a secret weapon. He was a swimmer. Kelly Crowley, a fellow hometown swim team member and Paralympian, told him about the Paralympic Games.

Two years after his diagnosis, Wise competed in the 2004 Athens Paralympic Trials in Minneapolis, Minn. “I was nowhere close to making the team. After the trials, I decided I wanted to go to the 2008 Beijing Paralympics. From that moment on, my whole life was swimming,” says Wise, who attended practices nine to 11 times a week and began eating a healthy “athletic” diet.  

At the age of 15, Wise made it to Beijing and swam in one event as a member of the U.S. Paralympic Team. Wise’s Mom credits swimming for her son’s miraculous survival in those early years.

“I love swimming — it has introduced me to some of my best friends. Swimming makes me feel normal. I know this may sound a little weird, but I train with two able teams both at my club and at college. Once I dive in the pool, I forget about my disease. I forget about all the negative doctor news. I forget about the ventilator,” says Joe. “The swimming pool is also the place where I can take my frustration out. Sometimes after hearing negative news from doctors I have the best practices of the year. I just take my anger out in the pool.”  

On to London, despite setbacks

Inspired by his experience as a Paralympian in Beijing, Wise immediately set a new goal to compete in not just one, but multiple events in London 2012.

Through the next four years of high school, Wise's mind flourished while his health continued to fail. In addition to an enlarged heart, he experienced weakness in his hips and diaphragm, and motility issues. By 2010, he needed treatments with a volume vent to deal with his enlarging heart. Despite his health issues, Wise's straight-A average and athletic abilities caught the notice of Loyola University Maryland, located in Baltimore. In 2011, he began college as a member of the school’s swim team.  

Just as he was closing in on his Paralympic goal, however, Wise’s condition “took a turn for the worse,” says his mom. His swim times slowed, his heart continued to weaken, his balance was poor, and he was spending more time on the vent. In February 2012, Wise's failing health forced him to take a medical withdrawal from college. “That was very tough — putting my education on hold and leaving my friends,” he says.

Refusing to give up hope, his doctors and his coaches promised, ‘We’re going to get you to London.” By early May, his health had dramatically improved. In June, he competed in the Paralympic trials and earned a place with the U.S. swim team.  

“The feeling I had when my name was called for the London team is almost indescribable. I felt ecstatic, and actually couldn't believe it. Three weeks prior to trials, I had one of the worst meets of my life. My coaches and I talked about if it was even worth going to trials in Bismarck, North Dakota,” Wise says. 

The 19-year-old will compete in five Paralympic events: 200-meter individual medley, 100-meter butterfly, 100- and 400-meter freestyle, and the 100-meter breastroke. 

“I have put the time, effort and hard work into this one goal. Considering the tough year I have had, just being on the team is a victory,” says Wise. “I have accomplished my goal. It just wasn't the road I wanted to take, but I guess God has a plan for everything and he was with me every step of the way.” 

After the London Paralympic Games, Wise will return to Loyola University Maryland to pursue a degree in political science with a minor in communications. He intends to continue swimming with the college team and help Loyola win a conference championship. “I plan on swimming to 2016 — I want to give my college coach four solid years of swimming,” he says. “I figure retiring in 2015 is way too close to a games year, so I will stick around for another year and hopefully make the [Paralympic] team and swim in Rio in 2016.”  

What are Wise’s long-term goals? He hopes to attend grad school and enter the world of politics working as a lobbyist for disability rights.  

Follow Wise’s adventures at the U.S. Paralympic Games on Facebook and Twitter, and learn more about his story in this 2008 video.

How to see the Games

The 2012 Paralympic Games will be held in London August 29 through September 9. They encompass 21 separate sporting events: archery, athletics, boccia, cycling road, cycling wheelchair, equestrian, football 5-a-side, football 7-a-side, goatball, judo, powerlifting, rowing, sailing, shooting, swimming, table tennis, sitting volleyball, wheelchair basketball, wheelchair fencing, wheelchair rugby and wheelchair tennis. A record 2.2 million tickets have been sold.

The Games can be watched in the U.S. via several outlets:

• The U.S. Paralympics YouTube channel is broadcasting 10 daily highlights of the games, interviews with the athletes plus the opening and closing ceremonies.
• Uninterrupted, live coverage will be aired on five channels on the International Paralympic Committee website.
• Paralympic.org will broadcast more than 1,000 hours of sporting action.
• NBC Sports Network (NBCSN) will air one-hour highlight shows on Sept. 4, 5, 6 and 11 at 7 p.m. EDT. NBC will broadcast a 90-minute special about the Paralympic Games on Sept. 16 from 2-3:30 p.m. EDT. All NBC and NBC Sports Network Paralympic highlight shows and specials will re-air on Universal Sports Network and UniversalSports.com.

For a wonderfully detailed overview of all sports at the Games, and a calendar of events, see The Paralympian: Paralympic Games Special Edition.

Martha Bhattacharya, a postdoctoral research scholar in developmental biology at Washington University School of Medicine in St. Louis, Mo., was awarded an MDA development grant totaling $180,000 over a period of three years to study how and why axons degenerate.

Axons are the long extensions of motor neurons (muscle-controlling nerve cells) that link up with muscles. Signals are sent down the axon to cause the muscle to contract. When an axon degenerates, it can no longer carry those signals, leading to weakness.

“In neuromuscular diseases where motor neuron dysfunction is the primary cause of disability, such as amyotrophic lateral sclerosis (ALS) and Charcot-Marie-Tooth (CMT) disease, axonal degeneration is a unifying pathological hallmark of disease progression,” Bhattacharya says.

To study axonal degeneration, she and her colleagues developed a fruit fly research model that allows the identification of necessary components of the axonal degeneration cascade. Using this system, she has identified several key steps in the process, including one involving a protein called G-protein coupled receptor (GPCR), and another called protein kinase.

“These receptors are highly desirable drug targets,” Bhattacharya says, and pharmaceutical companies have a great deal of experience designing drugs to influence their behavior. “For the GPCR, we will determine its signaling mechanism in mammalian neurons and test its ability to protect neuromuscular synapses after injury. For the kinase, we will examine the effects of loss of this protein on mouse axons and synapses,” the sites of information exchange between nerve and muscle.

Learning more about the details of axonal degeneration also will help researchers understand more about the entire disease process, potentially leading to other targets for therapeutic intervention.

Funding for this MDA grant began Feb. 1, 2013.

Mice with a disorder resembling the type 1B form of Charcot-Marie-Tooth disease (CMT) benefited from treatment with either of two forms of oral curcumin, a component of the spice turmeric, according to researchers supported in part by MDA.

Treatment with curcumin appeared to reduce the effect of a cellular defense mechanism — the unfolded protein response — which can lead to cell death. Curcumin-treated mice had better muscle function and more normal-appearing nerve fibers than untreated mice.

The newly published mouse results, which build on preliminary findings announced in April 2010, could lead to testing of curcumin derivatives in people with the type 1B form of CMT, and possibly in those with other types of CMT. Researchers cautioned that it’s very uncertain how many other CMT-causing mutations (there are hundreds) will respond to treatment with curcumin; however, promising results have been seen in mice with a mutation that causes CMT1E.

MDA provided funding to Michael Shy, a professor of neurology at the University of Iowa Carver College of Medicine, and co-director of the MDA neuromuscular disease clinic at the University of Iowa Hospitals & Clinics in Iowa City. (Shy was at Wayne State University in Detroit until early 2012, and much of this research was conducted there.) He and his colleagues published their findings in the December 2012 issue of the journal Brain.

CMT1B results from mutations in the MPZ gene

CMT1B results from any of a number of different mutations in the gene for the myelin protein zero (MPZ) protein.

MPZ is one of many proteins and fatlike substances found in myelin, an insulating sheath that surrounds nerve fibers and speeds the transmission of nerve signals, such as those that go from nerve cells to muscle cells.

When MPZ is malformed or deficient, the myelin sheath isn’t as effective as it needs to be for optimal nerve signal transmission. Mice and humans with MPZ mutations have sensory and motor abnormalities, particularly in the lower legs and forearms.

The mice in these experiments had a mutation in one of their two MPZ genes. The mutation is one that can cause human CMT1B, but is not the only mutation that can do so.

Shy said that, while the experiments described in the December paper were conducted in mice with one specific MPZ gene mutation, curcumin also may be useful with other mutations.

“Our results suggest that several MPZ mutations may respond to curcumin derivatives,” Shy said. “While it is true that the mutation in our mice is just one of the known CMT1B mutations, we already know that there are several others that have similar effects on cells and therefore may respond to a similar therapeutic approach.”

Curcumin treatment had multiple benefits

Compared to untreated animals, mice with a disorder mimicking human CMT1B that were treated with curcumin in sesame oil or with phosphatidylcholine curcmin:

• showed superior ability to hold onto a rotating rod, performing as well as mice without any disorder at 6 weeks of age;
• had larger-diameter sciatic nerve fibers;
• showed a more intact, healthier-appearing myelin sheath in the places where nerve fibers meet muscle fibers; and
• showed evidence that their myelin-making cells were better able to tolerate the abnormal MPZ protein made from the mutated MPZ gene.

Countering the ‘unfolded protein response’

A cellular defense mechanism known as the unfolded protein response, or UPR was reduced in the curcumin-treated mice. The UPR can protect cells from abnormally formed proteins but also can, in some situations, cause these cells to die.

The investigators speculate that reducing the effects of the UPR may protect cells and account for the beneficial effects of curcumin.

In an accompanying editorial in the same issue of Brain, author Rhys Roberts cautions that not all CMT mutations, and perhaps not even all CMT1B-causing mutations, lead to accumulations of misfolded proteins or to activation of the UPR, and that therefore the curcumin response may apply only to a small portion of the CMT population.

Roberts, a neuroscientist at the Cambridge Institute for Medical Research in the United Kingdom, notes that the mutation that affects the mice used in these experiments — known as the R98C mutation — is only one of more than 120 different CMT1B-associated mutations in the MPZ gene. He says it’s crucial to understand the effects of each mutation and to develop therapies based on these effects.

In separate communications, Shy said he agrees with Roberts but that he and his colleagues have examined the effects of nine CMT1B-causing mutations so far and have found that five of them activate the unfolded protein response, indicating that they might respond favorably to curcumin treatment.

In addition, he noted, a mutation that causes CMT1E— a different form of CMT, caused by a mutation in the PMP22 gene — falls into this category, and mice with this mutation also have been found to respond positively to oral curcumin.

“Our results suggest that MPZ mutations and possibly other mutations that activate the unfolded protein response may respond to therapies that reduce this activation,” Shy added.

“While it is true that the MPZ mutation contained in our mice reflects just one CMT1B mutation, we already know that there are at least several other CMT mutations in which the unfolded protein response is activated.

"We are currently working to determine how many of the other MPZ mutations activate this potentially harmful defense mechanism and whether these mutations or similar mutations in other forms of CMT may respond to a similar therapeutic approach."

Ronald Liem, professor of pathology and cell biology at Columbia University Medical Center in New York, N.Y., was awarded an MDA research grant totaling $318,264 over a period of three years to study the progression of disease in a mouse model of type 2E Charcot-Marie-Tooth (CMT) disease.

CMT is the most commonly inherited neurological disorder, affecting 1 in 2,500 people worldwide. It is a slowly progressive disorder, causing degeneration of the peripheral nerves that control sensory information coming from the limbs. CMT2E is caused by mutations in the gene for a protein called neuronal intermediate filament light (NFL). NFL provides stability to axons, the long extensions of muscle-controlling motor nerve cells called motor neurons that allow them to control muscle contractions.

Liem’s lab has created a mouse model of CMT2E by introducing a mutated copy of the gene. Their preliminary results indicate the mouse develops many of the same features as people with the disease, including deficits of movement and hearing. “We believe that this new mouse model is likely the best model of CMT type 2E and will allow us to study the progression of the disease at a level that is not possible in human subjects. We expect that the mouse model will also be useful for testing therapeutic compounds when they become available,” Liem says. 

Liem will be performing detailed developmental and anatomic studies to follow the progression of the disease in mice, and to learn more about exactly how the mutation causes problems. One focus will be on the effects of the mutation on mitochondria, the cell’s "powerhouses," which are believed to be involved in CMT.

“These studies will give us a better understanding of the mechanisms by which nerve damage occurs as a result of this mutation,” Liem says. “We expect that the mouse model also will be useful for testing therapeutic compounds when they become available.”

Funding for this MDA grant began Feb. 1, 2013.

Vera Fridman, at Massachusetts General Hospital in Boston, was awarded an MDA clinical research training grant totaling $180,000 over a period of two years to the effects of Serine in people with a form of Charcot-Marie-Tooth (CMT) disease called hereditary sensory and autonomic neuropathy type 1 (HSAN1).

CMT is the most commonly inherited neurological disorder, affecting 1 in 2,500 people worldwide. It is a slowly progressive disorder, causing degeneration of the peripheral nerves that control sensory information coming from the limbs. HSAN is a rare genetic neuropathy that causes severe numbness, weakness and ulceration of the feet and hands.

Two abnormal lipids (fat-like substances) have been identified in the blood of both humans and mice with HSAN1. It has been shown that levels of these lipids can be reduced by administering the amino acid serine, and that mice treated with serine have better motor and sensory function.

Fridman’s goal is to determine the effect of serine on symptoms of people with HSAN1 in order to assess whether serine supplementation may be an effective therapy for the disease.

Funding for this MDA grant is effective July 1, 2013.

The Muscular Dystrophy Association has awarded 44 new grants totaling $13.6 million to advance the understanding and treatment of neuromuscular diseases. The new grants, most of which took effect Feb. 1, encompass a range of diseases covered by MDA’s research program, and they support innovative approaches to basic research and new drug development.

In addition to addressing 16 specific neuromuscular diseases under MDA’s umbrella, the grants also fund research into muscular dystrophy in general, and research into muscle physiology related to neuromuscular disease.

To learn about each new grant, visit the Winter 2013 Grants at a Glance slideshow.

Major themes

Many of the projects funded by this new round of MDA grants fall into four broad categories:

1. Understanding the relationship between specific genetic mutations and disease manifestations. A number of grants enable researchers to look at specific genes that are known to cause disease and determine what the mutation in that specific gene does.

“MDA-funded research has made amazing advances in identifying genes that relate to diseases, but there is still a lot to be learned about how those genes cause the characteristics of the disease,” said Jane Larkindale, MDA vice president of research. “Gaining this understanding gives us a host of new therapeutic targets — a major part of MDA's research focus.”

2. Early-stage testing of specific therapeutic hypotheses. MDA is funding researchers to screen for and test molecules that might be able to be turned into therapies.

“While basic research gives us hypotheses about how we might be able to treat a disease, these projects test those hypotheses,” said Larkindale. “Is the mechanism important? Is there is a target worthy of building a drug around? The results of these projects could lead to drugs that we can test or to new therapeutic targets.”

3. Understanding the processes of degeneration and regenerationin muscles and in nerves. MDA-supported researchers will closely examine the process of deterioration and regrowth in axons (nerve fibers), muscle and the muscle membrane.

“Most of the diseases under MDA’s umbrella are diseases of degeneration, either because there is too much degeneration, not enough regeneration or both,” Larkindale said. “Studies like these are looking for the mechanisms by which these processes are regulated, and how we can tip the balance in a favorable direction.”

4. Developing more efficient diagnostics for neuromuscular diseases. These grants fund the development of better screening techniques for diagnosing disease, including newborn screening technology for Duchenne muscular dystrophy (DMD).
   
“One of the advantages to being an ‘umbrella organization’ that covers many types of neuromuscular disease is that we can fund individual research projects that can tell us about several diseases,” Larkindale noted. “For example, our grant to John Manfredi of Sfida BioLogic to investigate small molecules that promote the growth of axons of motor neurons in spinal muscular atrophy also may shed light on other diseases of axon degeneration, such amyotrophic lateral sclerosis and Charcot-Marie-Tooth (CMT) disease. Similarly, Noah Weislander at Ohio State University is taking a drug that’s in development for DMD and applying it to limb-girdle muscular dystrophy.”

Disease-specific grants

Amyotrophic lateral sclerosis (ALS): A number of new grants fund strategies for drug development and the search for new genes that are implicated in the disease. For more on ALS grants, see Grants Support Study of New Genes, New Drug Discovery Strategies for ALS.

Becker (BMD),Duchenne (DMD)andlimb-girdle (LGMD) muscular dystrophies: New grants support several research projects aimed at investigating newly discovered repair pathways and giving these pathways a "boost" to try to reduce muscle damage.  

In addition, DMD and BMD research projects include:

• increasing levels of utrophin, a protein similar to dystrophin;
• developing a better understanding of the beneficial effects of sildenafil, a drug that improves blood flow to muscles and has shown promise in muscular dystrophy;
• improving techniques for generating and transplanting muscle cells; and
• developing novel therapeutic strategies, including microRNAs and heat shock proteins.

Charcot-Marie-Tooth disease (CMT): Researchers will study the progression of disease in a mouse model of one form of CMT to learn more about how that mutation causes problems. One focus will be on the effects of the mutation on mitochondria, the cell’s powerhouses, which are believed to be involved in CMT.

Congenital muscular dystrophy (CMD) and LGMD: In many cases of CMD and LGMD, the gene causing the disease is unknown. By analyzing the RNA (a chemical cousin to DNA) in cells, researchers hope to discover new mutations that cause these diseases, leading to better diagnosis and targets for new treatments.

Congenital myasthenic syndrome (CMS): Scientists will use high-resolution imaging technologies to study the mechanisms underlying the dysfunctions seen an animal model of CMS. These images will be used to better understand the defects caused by the gene at the neuromuscular junction, where muscle and nerve interact.

Distal muscular dystrophy (DD): Laing distal myopathy is an inherited muscle disease characterized by early and selective weakness of the lower leg that affects ankle and great toe bending. With time, the disease progresses to other muscles, including those of the neck and face. It is caused by mutations in the gene for a muscle protein that helps create the pulling force that allows muscles to contract. Researchers will explore how the disease-causing mutation prevents normal interaction of muscle proteins, and will create a mouse model in order to better study the effects of mutation and to test potential therapies.

Dysferlinopathies: Dysferlinopathies are a group of muscular dystrophies (including LGMD2B and Miyoshi myopathy) caused by mutations in the dysferlin gene, which carries instructions for the dysferlin muscle repair protein. Researchers will explore how calcium signaling differs between healthy cells and those lacking dysferlin, leading to better understanding of the disease process and options for therapy development.

Friedreich’s ataxia (FA): One project targeting FA will develop new research models and explore new therapeutic approaches for the disease. In this project, the DNA carrying the FA mutation will be “edited” to correct the mutation, using new molecular tools. This will allow comparison of cells with and without the mutation that are otherwise genetically identical. A second project will study ways to overcome the vulnerability of heart muscle in the disease. That vulnerability involves mitochondria, the cell’s energy producers, which may be deficient in their ability to use fats and sugars as fuels. Overcoming that deficiency may be a viable therapeutic strategy.

Facioscapulohumeral muscular dystrophy (FSHD): FSHD is caused by mutations that cause production of a toxic protein called DUX4. One group of researchers will be searching for changes in muscle and blood proteins that occur in FSHD, hoping to find a biomarker (biological indicator) that can be used to track response to therapy in future clinical trials. Another group will use gene-editing tools to correct mutations in patient cells, and compare muscle development between uncorrected and corrected cells, in order to shed light on the molecular mechanisms underlying FSHD.

General muscular dystrophies and muscle physiology: Several new grants fund projects that may lead to insights applicable to many muscle diseases. That may be case for a vitamin A-like molecule that blocks two different pathologic processes in muscle: formation of bone within the muscle and muscle degeneration. Scientists will be conducting experiments to learn more about this molecule’s effects and exploring whether it has potential for treatment of muscular dystrophy. Other scientists will be pursuing a cell transplantation strategy in which skin cells are first transformed into muscle cells. They will be working to optimize cell delivery and survival strategies, as well as exploring whether treating cells before transplantation with a regulatory gene can improve the long-term success of the transplant.

Inclusion-body myositis (IBM): Three groups will be exploring aspects of IBM, and its overlap with ALS. Mutations in a gene called VCP are one cause of both diseases. One group is exploring the possibility that VCP may be involved in a gene regulatory system that fails when the gene is mutated. Another group will be using state-of-the-art gene hunting techniques to find other genes that cause IBM, in order to better understand its causes and potential therapies. A third group will be focusing on the protein aggregates found in both VCP and ALS, which are believed to indicate an ongoing toxic process within the cell, and may be toxic themselves. By studying the aggregation process in yeast, scientists hope to better understand how aggregation leads to disease, and whether the aggregates can be targeted with new therapies.

Myotonic muscular dystrophy (MMD, also known as DM): Two projects will take aim at MMD. One project will develop better diagnostic tools that should allow doctors to offer their patients much more detailed information about the likely clinical course of the disease and the likelihood of it developing in those not yet affected. The other project will test the ability of compounds to target the toxic RNA that causes the disease, an early step in drug development.

Oculopharyngeal muscular dystrophy (OPMD): OPMD is caused by mutations in the PABPN1 gene. Researchers will use a fly model of the disease to understand how the mutation leads to the disease, a crucial step in developing therapy.

Mitochondrial myopathies (MM):In people with a mitochondrial myopathy, some mitochondria are mutated and function poorly, while others are healthy. Researchers will explore whether these diseases can be treated by encouraging cells to degrade their unhealthy mitochondria, thus promoting reproduction and growth of nonmutated mitochondria.

Myasthenia gravis (MG): MG comprises several related diseases, all involving anautoimmune attack on the neuromuscular junction (where signals are passed between nerve and muscle). In autoimmune diseases, the immune system mistakenly attacks the body's own tissues.

One research group will better characterize the immune regulatory system that goes awry in the disease, allowing antibodies to attack the body's own proteins at the neuromuscular junction. A second group will study a new animal model of one form of MG, called anti-MuSK myasthenia (AMM), to understand the progression of the disease and options for therapy. A third group will develop tools for diagnosis of the low-density lipoprotein receptor-related protein 4 (LRP4) form of MG.

Spinal muscular atrophy (SMA): The gene defect in SMA is known, but there is still much to be learned about how it causes disease. Scientists will examine the protein product of the gene to discover how it moves through the cell and identify the other molecules with which it interacts. The long extensions of motor neurons called axons are a particularly important target in SMA because they degenerate before the neuron dies; improving their survival is the goal of another MDA grant. Still other researchers will test whether therapy must be given early in the course of disease to have a beneficial effect, an important unknown question as new treatments are tested.

Details about each of these new grants are given in the Winter 2013 Grants at a Glance slideshow.

Richard Robinson is a freelance medical and science writer based in Sherborn, Mass.

As scientists learn more about what our DNA can tell us about health and disease, public interest has intensified and genetic testing has become increasingly common. In response, the American Academy of Pediatrics (AAP) and the American College of Medical Genetics and Genomics (ACMG) have released new guidelines to address updated technologies and new uses of genetic testing and screening in children.

New recommendations address diagnostic and carrier testing; newborn screening; predictive genetic testing (which may identify a child’s risk of developing later- or adult-onset conditions); histocompatibility testing (sometimes referred to as “tissue matching”); adoption; the sharing of test results; paternity testing; and direct-to-consumer testing, which refers to tests marketed directly to the public.

Those considering genetic testing should speak with their physician.

Genetic testing in newborns and children

According to the AAP, approximately 4 million infants in the United States undergo newborn screening, which is designed to detect abnormalities for which a treatment is available and which would benefit from being treated early, before symptoms begin.

Genetic testing of children past the newborn stage is not as common. It’s most often used to diagnose genetic conditions in children who have signs or symptoms, or to inform treatment decisions.

Testing may also be performed on children who don’t have symptoms, but whose family history includes instances of a specific genetic condition — particularly if early treatment can affect quality of life or life span.

The child’s best interests always should come first

In their general recommendations, both the AAP and ACMG noted that with DNA testing, the best interests of the child always should come first. Additionally, they recommend that genetic counseling accompany genetic testing, as clinical geneticists, genetic counselors or other health care providers with appropriate training and expertise can help obtain and interpret test results.

In addition, the two groups recommend the following:

Diagnostic testing may be done to diagnose disease in children who have symptoms of a genetic condition, or to help determine proper therapy. In these cases, parents should be informed about any risks or benefits. Their permission — as well as the assent of the child, when appropriate — must be obtained.

Newborn screening (NBS) should be offered for all children. Parents should be advised of NBS benefits, risks and the steps that follow abnormal screening results. The decision of informed parents to refuse the procedure should be respected.

Unless it can lead to health benefits during childhood, carrier testing should not be performed on children. Genetic testing or screening for carrier status should be offered to pregnant adolescents or adolescents who are considering having children when clinically indicated, and the risks and benefits should be explained clearly.

Parents may authorize predictive genetic testing for children who don’t have symptoms but are at risk of childhood-onset conditions. Testing for adult-onset conditions should wait unless interventions made during childhood can offer benefits. Exceptions may be made in cases where diagnostic uncertainty poses a significant psychosocial burden.

Histocompatibility testing (also known as tissue compatibility or tissue-matching) is permissible when it benefits immediate family members, but the interests of the child should be safeguarded and such testing only should be conducted after psychosocial, emotional and physical implications have been considered.

Adoption: For adopted children, and those awaiting adoption, the same considerations for genetic testing of biological children should apply. It should be recognized that predictive genetic testing before adoption may be in a child’s best interests, as it can help ensure his or her placement with a family capable of handling the potential medical circumstances.

Disclosure: Children should be informed of their test results at an appropriate age. Under most circumstances, a request by a mature adolescent for test results should be honored. In addition, results from genetic testing of a child may have implications for the parents and other family members. Health care providers have an obligation to inform parents and the child, when appropriate, about such implications; they should encourage patients and families to share this information and offer to help explain the results to the extended family or refer them for genetic counseling.

AAP and ACMG strongly discourage the use of direct-to-consumer and home-kit genetic testing of children, due to a lack of oversight on test content, accuracy and interpretation.

For more information

Full reports from both the AAP and ACMG are available online for free. 

The AAP summary report, Ethical and Policy Issues in Genetic Testing and Screening of Children, was published online Feb. 21, 2013, in Pediatrics.

The ACMG policy statement, which provides ethical explanations and empirical data in support of the new recommendations, also was published online Feb. 21, 2013, in Genetics in Medicine. Read the full report titled Technical Report: Ethical and Policy Issues in Genetic Testing and Screening of Children.

Also see:

• The Pain and Promise of Prenatal and Newborn Genetic Diagnosis (Quest, July 1, 2007); and
• Screening Newborns for Neuromuscular Diseases Has Pros and Cons (MDA newborn screening resources).

Additional information on newborn screening is available at the website for the Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children.

The Muscular Dystrophy Association’s annual conference being held in Washington, D.C., on April 21-24, 2013, is centered on the theme Therapy Development for Neuromuscular Diseases: Translating Hope into Promise.

"Five years ago, this meeting couldn’t have happened," said Jane Larkindale, MDA's vice president of research. "We couldn’t have filled two-and-a-half days with the kinds of presentations we have now. The agenda is packed with important talks discussing everything from early-stage therapeutic targets through to clinical trial results, along with sessions discussing the development of new tools that will allow us to conduct trials more effectively." 

The conference is aimed at professionals and is not open to the public. However, blogs and reports will be available to all on the meeting website, both during and after the proceedings.

Nearly 500 attendees from academic laboratories, clinics and industry are expected, with more than 60 platform presentations and more than 200 poster presentations planned.

The goal, said Larkindale, is to “identify barriers to therapeutic development and how to overcome those barriers.”

Conference co-chairs are C. Frank Bennett, CEO of the biomedical company Isis Pharmaceuticals, and Eric Hoffman, director of the Research Center for Genetic Medicine at Children's National Medical Center in Washington, D.C.

From targets to trials

Conference presentations have been organized into broad themes relating to therapy development.

Targets: These presentations will focus on identifying molecular targets at which to aim therapies in different disorders, such as amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth disease (CMT), facioscapulohumeral muscular dystrophy (FSHD), myotonic muscular dystrophy (MMD) and spinal muscular atrophy (SMA).

Genetic modifiers: Presentations will explore naturally occurring gene variations that modify the course of diseases and can help explain an individual's disease course, as well as provide targets for therapeutic development, in disorders such as ALS, Becker muscular dystrophy (BMD), Duchenne muscular dystrophy (DMD), SMA and MMD.

Therapeutic modalities: Presentations will focus on different types of compounds that have the potential to be developed into therapies, such as stem cells, proteins, small molecules and antisense, with particular application to ALS, one form of congenital muscular dystrophy (CMD), DMD and FSHD.

Biomarkers: Presentations will discuss the identification and use of biological indicators, including imaging studies, which may reflect the progress of a disease or its response to treatment, with particular application to ALS and DMD.

Animal models: Discussions will center on research animals that replicate the characteristics of various human neuromuscular diseases and how they can be used to study these diseases, with particular application to ALS, centronuclear myopathy (CNM), DMD, Emery-Dreifuss muscular dystrophy (EDMD) and SMA.

Use of animal models in drug development: Presenters will explore how well animal models of human disorders can be used to develop drugs, with particular application to ALS, DMD FSHD, myotubular myopathy (MTM) and SMA.

Preclinical work for trial design and regulation: Designing laboratory studies that can serve as the foundation for human trials of investigational drugs will be focus of these talks.

Clinical trials: These presentations will include updates on trials of tirasemtiv in ALS; drisapersen and eteplirsen in DMD; cardiac treatments for DMD; RG2833 for Friedreich's ataxia (FA); and ISIS-SMNRx for SMA.

The latest and greatest: Discussions will include late-breaking research reports, with particular application to CNM, DMD, FA and mitochondrial myopathies.

Resources for drug development: Topics to be covered include working with the National Institutes of Health's National Center for Advancing Translational Sciences (NCATS), tissue banks, stem cells, databases, and computer chips, with particular application to ALS.

For more information

To learn more and to read blogs and reports during and after the meeting, see the MDA Scientific Conference home page.

This conference is the third in MDA's conference series, which features scientific (research-oriented) conferences in odd-numbered years, and clinical (care-oriented) conferences in even-numbered years.

Turning neuromuscular disease research into treatments as quickly and effectively as possible was the overarching theme of dozens of formal presentations, nearly 200 scientific posters, and countless informal conversations at the MDA Scientific Conference, April 21-24.

A palpable sense of excitement pervaded the sold-out event thanks to the unprecedented number of experimental treatments in clinical trials for neuromuscular diseases, and the unique opportunity the conference provided for information-sharing and collaboration among scientific professionals from many disciplines.

“This is one of the few times that researchers from the different fields of muscular dystrophy get together and compare notes in one place at one time,” commented Ken Hensley, an ALS researcher from University of Toledo Medical Center. “It’s a very focused, intense meeting where we can share the latest in applied and basic biology.”

Conference attendees included a number of younger researchers.

The biennial conference, held for the first time in Washington, D.C., drew more than 500 participants from the academic, corporate drug development and clinical arenas. (The conference was not open to the general public.) A larger-than-ever number of young researchers were among the attendees this year — a statistic cited by more than one participant as a positive sign for the future of neuromuscular disease research. 

Sharing ideas across diseases a priority

Capitalizing on MDA’s unique status as an umbrella organization covering more than 40 neuromuscular diseases, the tightly packed agenda focused on common research themes rather than individual diseases.

Sessions were built around such themes as targets for drugs, genetic modifiers, therapeutic modalities, biomarkers, animal models, preclinical work and clinical trials.

Each session featured presentations from researchers working in different neuromuscular diseases, enabling the widest possible sharing of knowledge and ideas.

There was “a real sharing of unpublished data,” said Kay Davies of the University of Oxford, who is working on a treatment for Duchenne muscular dystrophy (DMD). “People [were] willing to give their ideas and really fight each other to find out which is the best way. Good competition for the same goal. That’s the way we’re going to succeed.”

A rapidly changing research landscape

A significant amount of research data, published and unpublished, was shared during the two-and-a-half day conference, both from completed trials and trials-in-progress.

“[Research] is going exhilaratingly fast,” said Christopher Pearson of the Hospital for Sick Children at the University of Toronto, who is studying a type of genetic mutation underlying several diseases in MDA’s program, including myotonic and oculopharyngeal muscular dystrophies and Friedreich’s ataxia. “In fact, it’s going so fast that I could spend much of my time reading other people’s work instead of doing my own work. It’s a very exciting time.”

"Cross talk" among researchers studying a variety of neuronmuscular diseases was a hallmark of the conference.

Many speakers made reference to the rapidly changing landscape of research, which has been altered by such factors as technological advances, improvements in clinical trial design, interest by the drug development industry, and the increasing power of the patient’s voice. A commonly heard refrain was “we couldn’t have held this conference five years ago.”

“Many pharmaceutical companies unexpectedly are now targeting ALS,” said Jeff Rothstein, director of the Brain Science Institute, and the MDA/ALS Center, both at Johns Hopkins University. “That wasn’t the case a few years ago. They’re very interested in the better science that we can do in ALS today — that is, using cells to discover therapies, using cells to find biomarkers so they can intelligently design trials.”

“It’s a very hopeful time,” agreed Hensley. “Not only is there incredible scientific knowledge that’s blooming forth about the basic origins of these diseases … but there really is a change in the landscape in the way clinical trials are designed, the way that regulatory committees and agencies look at orphan disease therapy development — a whole ‘sea change’ in the way pharmaceutical companies are viewing orphan diseases as an attractive target for new therapeutic technologies.”

Poster session award winners

In addition to more than 70 session presentations, some 200 scientific posters were displayed at the conference, detailing the results of experiments and trials in a wide range of diseases.

Several posters by research trainees were selected for awards:

• Nicolas Wein, “Alternate translational initiation and amelioration of phenotype in the DMD gene.”
• Shin, Ji-Yeon Shin, “Emerin-LAP1 double knockout mice: a small animal model of X-linked Emery-Dreifuss muscular dystrophy.”
• Yun-Sil Lee, “Muscle hypertrophy induced by follistatin and Acvr2B/Fc accelerates degeneration in dysferlin mutant mice” (limb-girdle muscular dystrophy (LGMD), distal MD.

About the MDA Scientific Conference

Conference co-chairs Eric Hoffman (left) and C. Frank Bennett presided over the event.

Co-chairing the conference were C. Frank Bennett, CEO of the biomedical company Isis Pharmaceuticals, and Eric Hoffman, director of the Center for Genetic Medicine Research at Children's National Medical Center in Washington, D.C.

The event was made possible by the generous support of a number of sponsors.

• Platinum sponsor: Sanofi, Bridgewater N.J.
• Gold sponsors: Biogen Idec, Weston, Mass.; and Sarepta Therapeutics, Cambridge, Mass.
• Silver sponsors: Catabasis, Cambridge, Mass.; Cytokinetics, South San Francisco; Fate Therapeutics, San Diego, Calif.; Pfizer, New York; Shire, Dublin, Ireland; PTC Therapeutics, South Plainfield, N.J.; and Tivorsan Pharmaceuticals, Providence, R.I.
• Additional thanks to: ARMGO Pharma, Tarrytown, N.J.

To learn more about the conference, see:

• Conference agenda
• MDA Scientific Conference Blogs (for personal perspectives on the proceedings)

MDA holds scientific conferences in odd years and clinical (health-care-focused) conferences in even years. (Visit the MDA annual conference series home page for an overview of the series.)

In summary

The many reasons for holding an MDA scientific conference were underscored on the last day of the event in a speech made by Vance Taylor, 35, a homeland security consultant in Washington, D.C., who has LGMD.

Taylor showed conference attendees photos of his wife and two children, and then declared: “I want you to give me 50. Not 50 push-ups. Fifty years. I need to make it to my 50th birthday.”

In order to cover the large amount of science reported at the conference, in the coming weeks MDA will be posting new articles and updating older articles with new information. Be sure to check mda.org for the latest neuromuscular disease research news.

An MDA-supported trial of high-dose ascorbic acid (vitamin C) in the type 1A form of Charcot-Marie-Tooth disease (CMT) (CMT1A) did not find a benefit for this treatment, although it appeared safe and was generally well-tolerated. There were no serious adverse events judged to be related to the study drug.

Despite the disappointing results, the trial did have a positive effect on future trials in CMT, say the researchers. It resulted in the development of the necessary infrastructure to coordinate and conduct multicenter trials; helped improve trial design in CMT; and utilized ratings scales designed to measure CMT symptom severity.

The trial was conducted at sites at Wayne State University in Detroit, Johns Hopkins University in Baltimore and the University of Rochester in New York.

MDA grantee Richard A. Lewis, now at Cedars-Sinai Medical Center in Los Angeles and at Wayne State University in Detroit during this trial, with colleagues, published the results June 24, 2013, in JAMA Neurology.

An accompanying editorial, also published June 24 and authored by Pragna Patel at the University of Southern California in Los Angeles and David Pleasure at the University of California, Davis, discusses the study and probes new directions for drug treatment of CMT1A.

CMT Neuropathy Score was main outcome measure

The high-dose ascorbic acid trial in CMT1A included 110 participants, ages 13 to 70, with this disorder. They were randomly assigned to receive eight capsules of 500 milligrams each of ascorbic acid per day, or placebo capsules that looked the same as the ascorbic acid capsules.

Four times as many participants were assigned to ascorbic acid as were assigned to the placebo.

Using primarily the CMT Neuropathy Score (CMTNS), a standardized scale to measure the effects of CMT, the investigators compared the scores of 87 participants receiving ascorbic acid, 23 participants receiving placebo capsules, and 72 "natural history" controls — untreated people with CMT1A who were part of an earlier study.

The investigators analyzed changes in the CMTNS and other measures over the course of two years, comparing the two groups in the current study to each other and to a natural history group.

The CMTNS measures motor and sensory function, strength and electrical signals from muscles and nerves. Higher scores reflect more severe disease symptoms. Reductions in a score represent improvement.

Placebo and ascorbic acid groups improved

The natural history group had worsened, on average, by +1.33 points on the CMTNS over two years. Surprisingly, however, both the placebo group and the ascorbic acid group in the current study did much better on this scale than the natural history group. In fact, both groups improved slightly (showing lower scores than at baseline) after two years, with the placebo group improving a little more (score reduced by -0.92 points) than the ascorbic acid group (score reduced by -0.21 points).

Overproduction of a protein called PMP22, which forms part of the sheath that surrounds nerve fibers, is the biological cause of CMT1A. Therefore, the investigators also measured levels of genetic instructions for PMP22 in skin cells in 69 trial participants — 55 in the ascorbic acid group and 14 in the placebo group. No effects of the treatment were detected.

"Subjects had better outcomes than those reported in natural history studies," the authors of the June 24 publication write, adding that "the concurrent [during this trial] placebo group, though small, had better-than-expected outcomes over a two-year period."

They conclude that it is "unlikely that 4 grams/day ascorbic acid has a clinically meaningful effect upon the course of CMT1A over a two-year period."

Mouse study looked promising

The original incentive for the current trial was a 2004 study conducted in France that showed that mice with a disease resembling CMT1A showed improvements in function when given ascorbic acid. The researchers on the mouse study also found evidence that the treatment reduced overproduction of the PMP22 protein.

The promising mouse results led to several trials of ascorbic acid in people with CMT1A, most of them at dosage levels lower than 4 grams per day. None showed clear benefit, but a trial conducted in Australia in 81 CMT1A-affected children showed a low dose of ascorbic acid might have improved function in some of them.

Lessons learned

The investigators on the current study note in their publication of the results that the high-dose CMT1A ascorbic acid trial pointed out some potential pitfalls that should be recognized in the design of future trials. They note that:

• a natural history control group may not be an accurate reflection of the current natural history of a disease, particularly if the group is not derived from similarly designed former trials; and
• assigning treatment-to-placebo participants in a ratio of four to one (four times as many treatment participants as placebo participants) may have biased the study toward a "placebo effect," meaning those on the placebo thought they had a good chance of being on the drug and may have performed better because of that perception.

The investigators also note the important strides made in the ability to conduct multicenter CMT studies as a result of conducting this trial. They note that:

• before this high-dose ascorbic acid trial, there was no infrastructure in place to conduct large-scale, multicenter trials in CMT;
• such an infrastructure was developed to conduct this trial and is now in place for future trials;
• a new version of the CMTNS was developed as the ascorbic acid trial was nearing completion; and
• the CMT Pediatric Scale, which measures physical functioning in children with CMT, was developed (with MDA support) as the ascorbic acid trial was nearing completion.

Registry seeks participants for future studies

The Rare Diseases Clinical Research Network, funded by the National Institutes of Health, invites families with CMT1A, CMT1B, CMT2A, CMTX, CMT4 or other known or unknown forms of CMT to join an online "contact" registry that asks for information such as your or your child's name, address, date and place of birth, email address and items relevant to your or your child's disorder.

The registry, developed in part with MDA involvement, is designed to help researchers identify and recruit potential participants for future research studies.

Kleopas Kleopa, professor at the Cyprus Institute of Neurology and Genetics in Nicosia, Cyprus, was awarded an MDA research grant totaling $280,945 over a period of three years to develop gene therapy in a mouse model of X-linked Charcot-Marie-Tooth disease (CMT).

CMTX is due to mutations in the gene for connexin 32. This protein forms connections between layers of the insulating material around nerve cells, called myelin. Loss of connexin prevents the nerve cell from functioning properly, leading to muscle atrophy, weakness and sensory loss in the limbs. Kleopa has generated a mouse model of the disease, and has developed virus-like particles that can carry a functional copy of the gene, increasing connexin 32 protein production when delivered directly to the nerve.

Now, Kleopa will study a combination of gene delivery methods, including direct injection into the nerves, muscles and spinal cord. He also will examine treated mice for signs that the gene improves neuropathy (nerve abnormalities).

“Transgenic mice are particularly well suited for this study because treatment of peripheral neuropathy can only be validated in a vertebrate animal model, where the pathology can be studied in peripheral nerves,” Kleopa says. “Furthermore, this particular mouse model reproduces all major pathological aspects of the human disease, and therefore it is relevant to test potential treatments.

“In the last two decades research in the field of inherited neuropathies, especially the common forms, has provided many insights into the causes and mechanisms of disease. Developing genetic treatments, using the recently generated disease models, is an important and timely approach to also provide potential therapies for these disorders in the near future.”

Funding for this MDA grant began August 1, 2013.

Charlotte Sumner, associate professor of neurology and neuroscience at Johns Hopkins University School of Medicine in Baltimore, Md., was awarded an MDA research grant totaling $300,000 over a period of three years to study the effects of the gene that causes one form of Charcot-Marie-Tooth disease (CMT).

CMT is characterized by the degeneration of peripheral nerves, resulting in disabling muscle weakness and sensory loss. One form of the disease, called type 2C CMT (CMT2C), is caused by mutations in a gene called TRPV4 that helps control the flow of calcium in and out of cells. “Our long-term goal is to determine how mutations in TRPV4 lead to CMT2C and to develop treatments for this disease,” Sumner says.

Some effects of these gene mutations are known, but how they cause nerve degeneration is still unclear. Sumner has generated fly and mouse models of CMT2C in order to pursue that question. “The advantage of using fruit flies is that they allow us to rapidly evaluate the effects of multiple mutations and potential disease modifiers, as well as to assess TRPV4 function by calcium imaging.” The mouse, in turn, better mimics aspects of human physiology affected in the disease and can be used to test drugs.

“Together, these studies will provide important insights into the cellular and molecular mechanisms underlying TRPV4-mediated nerve disease, and in the future, we plan to use these fly and mouse models synergistically to develop new therapeutic interventions,” she says. “Because it is an ion channel expressed at the cell surface membrane [and therefore potentially accessible by therapeutic compounds], TRPV4 inhibition represents an attractive therapeutic strategy for patients with CMT2C.”

Funding for this MDA grant began August 1, 2013.

Peter Hiesinger, associate professor at the University of Texas Southwestern Medical Center in Dallas, was awarded an MDA research grant totaling $300,000 over a period of three years to investigate the causes of type 2B Charcot-Marie-Tooth disease (CMT2B).

CMT2B is caused by mutations in a gene called rab7. The protein made from the gene performs a critical function in the degradation of debris in all cells. “Even though the gene is known, it is unclear how the mutations found in patients affect the gene’s function,” Hiesinger says. Without knowing how the mutation causes disease, it is difficult to design a therapy to treat it. He has developed models of the disease that suggest the mutation causes the protein to no longer be active, and that this loss of function affects nerve cells before other cells in the body.

“Our findings explain the genetic dominance [only one mutant copy of the gene, from either parent, is needed to develop the disease] and reveal a particular sensitivity of nerve cells for a defect in debris removal,” says Hiesinger. “This discovery opens the door for an understanding and a potential therapy of CMT2B based on the molecular manipulation of the underlying cause.

“Importantly,” he adds, “we suggest an increase of rab7 function as a therapeutic opportunity, in contrast to the currently suggested reduction of mutant gene function.”

In this project, Hiesinger will test this hypothesis of disease in a fly model of CMT2B and investigate rab7 function in detail.

Funding for this MDA grant began August 1, 2013.

In its summer 2013 round of research grant awards, the Muscular Dystrophy Association aims to catalyze research progress in a dozen neuromuscular diseases, with an eye toward applying that knowledge to related muscle diseases, as well.

“A large number of our grants are investigating new therapeutic technologies,” notes Jane Larkindale, MDA's vice president of research. “These are 'platform' technologies, where successes can be transferred well beyond the specific disease in which they are developed and tested.”

The 31 new grants, totaling $8.5 million, were approved by MDA’s Board of Directors in July and took effect Aug. 1. The grants can be viewed in the Summer 2013 Grants at a Glance slideshowand links to individual grant descriptions (as well as to background materials) are included in the descriptions below

Disease-specific grants

Central core disease (CCD)

As science advances, new opportunities often arise to make progress in diseases that previously had stymied researchers. That’s the case in CCD. MDA is taking advantage of scientific advances in technology to fund three new grants that will better define the fundamental problems in CCD, and provide insights into new treatment targets.

• Scientists at the University of Colorado, Denver, are performing basic research to define the interaction of two proteins critical for muscle function— the dihydropyridine receptor, which “senses” the electrical signal from a nerve, and the ryanodine receptor, which controls the release of calcium ions to stimulate muscle contraction. Mutations in either one lead to CCD, as well as increase the risk of experiencing malignant hyperthermia, a potentially fatal reaction to certain anesthetic drugs. A better understanding of those interactions can help identify targets for experimental treatments in CCD.
• Researchers at the University of California, Los Angeles, are looking at the interactions of mutated and normal proteins in animal models, to better understand how mutation leads to disease symptoms.
• Scientists at the University of Rochester are studying calcium handling in the disease, and test potential drugs to normalize calcium release.

Charcot-Marie-Tooth disease (CMT)

CMT is a group of more than 30 diseases, all affecting peripheral nerves (those outside of the brain and spinal cord). Each form is caused by a different gene. However, while many genetic anomalies cause the disease, every case ends with damage to the same peripheral nerves.

Three new MDA grants support progress in understanding several of the rarer forms of CMT:

• Researchers at the Cyprus Institute of Neurology and Genetics in Cyprus are working to develop gene therapy for X-linked CMT (CMTX1), which is caused by mutations in a gene for a protein called connexin 32.
• Researchers at Johns Hopkins University are studying type 2C CMT (CMT2C), which is caused by mutations in a gene called TRPV4 that helps control the flow of calcium in and out of cells.
• Researchers at the University of Texas are studying the effects of mutation of the rab7 gene in the 2B form (CMT2B). 

Duchenne muscular dystrophy (DMD)

Gene editing is a strategy that targets the mutant sequence in the dystrophin gene that causes DMD, and harnesses elements of the cell’s own “quality control” system to correct the mutation. If successful, gene editing could replace the standard gene therapy approach of supplying a new gene. (For background information about two approaches to gene editing, see DMD: 'Permanent' Gene Repair Strategy Looks Good in Lab and DMD Gene Repair Strategy Takes Big Step Forward.)

Two new grants, to researchers at the University of California, Los Angeles, and Duke University, seek to advance gene editing strategies for DMD (see Carmen Bertoni and Charles Gersbach grants).

Lessons learned in these gene editing studies will have implications for virtually all neuromuscular diseases, since most are caused by a defective gene.

Exon skipping for DMD is another therapeutic approach that has the potential to be effective against other neuromuscular diseases. Like gene editing, this approach doesn't rely on supplying a new gene, but rather works to make the existing gene more functional.

Exon-skipping compounds designed to address the most common DMD mutation (exon 51) are showing encouraging results in current clinical trials. As those trials continue, researchers in Murdoch, Australia, have received a new MDA grant to develop exon-skipping compounds for less common mutations in order to have those treatments ready to test pending the outcome of the exon 51 trials.

Other DMD-targeted grants focus on:

• The heart muscle in DMD. University of Washington/Seattle researchers are exploring strategies to reduce inflammation of the heart muscle as a way to reduce development of fibrous tissue within the heart. Another Seattle group, at the Fred Hutchinson Cancer Research Center, will pursue gene therapy for heart disease (cardiomyopathy) in DMD.
• Reduction of immune response to gene therapy. University of Pennsylvania researchers are studying the very earliest phases of the immune response, with the aim of reducing inflammation and improving the chances for successful gene therapy.
• Understanding muscle repair. Scientists at Duke University are studying muscle stem cells, called satellite cells, to determine the best way to increase their activity in replacing muscle cells. Other scientists — at George Washington University — are studying satellite cells in a mouse model of DMD and comparing their development to human satellite cells. Researchers at the University of Texas Southwestern Medical Center are investigating muscle precursor stem cells (myoblasts) to see how myoblasts develop into muscle fibers, an important step in replacing muscle cells lost in DMD. This research may lead to renewed interest in transplanting myoblasts or other cells for DMD therapy. Researchers at the University of California, Los Angeles, are exploring whether increasing the level of a muscle protein called sarcospan can stabilize muscle membranes, which are fragile due to the loss of dystrophin protein.
• Calcium handling in muscle. Scientists at the University of Pennsylvania are testing whether a new treatment that affects muscle calcium can slow damage to muscle tissue in several forms of muscular dystrophy. Calcium mishandling is a common problem in several muscle diseases, including DMD. The new treatment will be tested in models of DMD, Miyoshi myopathy, and myotonic muscular dystrophy.

Dysferlinopathies

Dysferlinopathies are muscle diseases caused by mutations in the dysferlin gene, an important muscle repair protein. They include limb-girdle muscular dystrophy and Miyoshi myopathy.

Unlike in Duchenne MD, anti-inflammatory steroidal drugs are not beneficial in these diseases. MDA’s grant to researchers at George Washington University supports tests of a new anti-inflammatory compound in a mouse model of dysferlinopathy. The drug was developed with MDA support by ReveraGen BioPharma for use in DMD.

If these efforts prove useful in the dysferlinopathies, they may have potential for other muscle diseases as well, including Duchenne muscular dystrophy, dermatomyositis, polymyositis, myasthenia gravis, and Lambert-Eaton myasthenic syndrome.

Facioscapulohumeral muscular dystrophy (FSHD)

Exciting new discoveries about the genetic cause of FSHD have yielded new targets at which to aim experimental treatments, with the goal of blocking the effects of the FSHD-causing mutation.

A group at the University of Washington in Seattle is exploring one biological pathway in FSHD that holds promise for drug treatment. The project will lead to a deeper understanding of the FSHD disease process, with the potential of determining the best way to intervene.

Myotonic muscular dystrophy (MMD, also known as DM)

MMD is caused by an abnormally expanded gene that leads to the buildup of RNA molecules in cells. These clumps of RNA cause problems by trapping a needed protein called muscleblind 1, which controls other genes.

With MDA help, two groups — one in Michigan and another in Texas — are developing “antisense” therapy that may be able to bind to excess RNA and prevent it from accumulating. (See Michael Pape and Thomas Cooper grants.)

Progress here also may aid in treatment of some forms of ALS (amyotrophic lateral sclerosis), which also may involve accumulation of excess RNA.

If antisense oligonucleotide therapy is found safe and effective, there will be great urgency to extend clinical trials to children with congenital myotonic dystrophy, a severe form of the disease that begins in infancy. However, not enough is known about the progression of congenital MMD.

To this end, an MDA-funded group in Salt Lake City is conducting a “natural history” study to collect information on the most critical symptoms of congenital MMD and how those symptoms change over time. This will allow for appropriate symptoms to be targeted in future trials, and help determine the most beneficial age at which to give treatments.

Another MDA grant focuses on a particularly challenging symptom of MMD — excessive daytime sleepiness. Researchers at the University of Florida, Gainesville, are attempting to define the molecular mechanisms that underlie abnormal sleep regulation in MMD, identifying the key genes responsible and developing new models of the disease.

Mitochondrial myopathies

Mitochondrial myopathies are caused by genetic defects in cell structures called mitochondria that process food molecules into the energy used by a muscle cell for all its functions, including contraction.

Scientists at Cornell University are testing whether dietary supplementation can be therapeutic in mitochondrial myopathies by bypassing the processing step that is impaired in the mitochondria.

Oculopharyngeal muscular dystrophy (OPMD)

OPMD primarily affects the muscles controlling the eyes and throat. To facilitate research in this disease, MDA is supporting scientists at Emory University who are developing a more accurate mouse model of OPMD that is closer to the human condition.

The new model will be the first to accurately mimic this disease in mice, providing a tool both for understanding how the disease affects muscle and for finding therapies.

Spinal muscular atrophy (SMA)

SMA symptoms are caused by the loss of muscle-controlling nerve cells called motor neurons. Scientists at the University of California, Los Angeles, are studying the development of motor neurons that control respiration, which are affected early in the infant-onset form of the disease (SMA1). One theory of motor neuron diseases is that the neurons that die earliest are the ones that are most vulnerable, a vulnerability that may arise during development. Researchers hope to learn more about normal motor neuron development and gain insight into the processes that may make respiratory motor neurons especially vulnerable.

A neuromuscular synapse is the connection between the motor neuron and muscle cell through which the motor neuron transmits signals that controls muscle contraction. One of the first events leading to motor neuron death is the loss of connection between neuron and muscle at the synapse. A team at Columbia University is studying how these synapses develop and how that process is disrupted in SMA.

Spinal-bulbar muscular atrophy (SBMA)

Two studies, both at the University of California, San Diego,  examine the important role of protein recycling in SBMA. Cells rely on a process called autophagy (awe-TOF-uh-gee) to break down and recycle large proteins and subcellular structures. Autophagy is critical for cell health, but relatively little is known about the process in motor neurons, the muscle-controlling nerve cells that are affected in SBMA and other diseases, including ALS and SMA. 

In SBMA, proteins misfold and accumulate in motor neurons. Autophagy should take care of these accumulated proteins before they cause problems, but the process appears to be disrupted in SBMA. The goal of both projects is to learn more about the regulators of autophagy in motor neurons and how that regulation goes awry in SBMA.

Insights from these studies will likely benefit work in ALS, in which misfolded proteins also accumulate.

MDA’s research program

“As research evolves, new ideas come to the fore in different diseases,” says MDA’s Larkindale. “MDA is committed to pursuing those new ideas in all the diseases in our program — and to leverage the progress in each of them to speed the best research in all of them.”

Les became a full-time artist at the age of 50. Unable to hold a paintbrush, he relied on his acclaimed "drip method" of painting. By dripping and pouring pools of different colors onto a canvas and maneuvering it with his hands, Les produced amazing patterns and dynamic images. This painting was donated to the MDA Art Collection in October of 2012 by Mr. & Mrs. John Victor whose family knew Les. It is displayed next to Les' painting "Mystical Peaks".

Alex was born in Uglich, Russia, and was adopted by Becky and Marshall Gravdahl. His mother is an artist and he began creating art in a variety of materials along with his brother Pasha, also from Russia. Alex also enjoys photography and playing the piano which he began at age three. He has won numerous awards for his artwork and photography at local fairs and festivals. He is currently selling a CD of his piano performances and selling his artwork in hopes of raising one million dollars for MDA.