MESSAGE FROM THE PRESIDENT Dear Friends, Some 50 years ago, a small group of parents, people with muscular dystrophy and their friends, started a volunteer organization to raise money for research into the causes of muscular dystrophy. You hold in your hands one of the fruits of that long-ago meeting. It’s with great pride that I present this DMD-BMD Special Report, which details the ground-breaking research and other important events taking place in the quest to treat and cure Duchenne and Becker muscular dystrophies. Looking through the pages of this report, I’m struck by how far we’ve come. As you learn about current and potential treatment strategies, advocacy efforts and the coordinated attack being mounted against these cruel diseases, there is every reason to hope that success is near. My motto always has been “together we can make it happen,” and this Special Report is a shining example that this is true. With every best wish, Gerald C. Weinberg President & CEO

THE HORIZON IS CLOSER

These are exciting times for muscular dystrophy researchers. Two decades after MDA-supported scientists tracked down the renegade gene that leads to Duchenne and Becker muscular dystrophies, the tireless efforts of the entire research community appear to be coming together in ways that offer real hope that meaningful treatments — and even cures — are within sight. Meanwhile, people with DMD and BMD are leading longer and heathier lives.

This special report provides information about current care strategies and several up-and-coming therapy approaches that aim to stop muscular dystrophy in its tracks.

RELIEF FOR TODAY — IMPROVING CURRENT CARE

Improved knowledge is the key to maximizing the benefit of existing treatments, preventing problems down the line, and enhancing and preserving vital functions.

Even as innovative treatments progress through testing, MDA continues to work closely with researchers, clinicians and patients to improve the quality of treatments that are at hand today.

THE TROUBLE WITH STEROIDS

Corticosteroids, such as prednisone, are still the mainstay of therapy for DMD (for detailed information on corticosteroids, see the May-June 2007 issue of MDA’s Quest magazine, available online at www.mda.org.)

Those who are on steroid programs know that along with muscle relief, these medicines bring a host of side effects. Weight gain, bone loss and mood swings are among the most troublesome. Aiming to reduce the side effects of steroids without sacrificing the health benefits, MDA has funded a five-year multi-institution study led by Diana Escolar at the Children’s National Medical Center. The study evaluates whether a high-dose weekly course of prednisone therapy is at least as effective as daily dose therapy for people with DMD, but with fewer side effects. The study has been completed, and results are expected this spring. Check the “What’s New” section of the MDA Web site (www.mda.org) for updates as they become available.

For further information, see www.clinicaltrials.gov/ct2/show/NCT00110669

KEEPING BONES STRONG

MDA is studying ways to reduce troublesome side effects of steroids, which offer many benefits in DMD and BMD.

MDA also is funding a separate study on the effects of long-term corticosteroid use on bone health in boys with DMD. DMD patients on corticosteroids are especially prone to bone fractures. Investigators hope the study will help them learn how to mitigate this adverse effect of these drugs. Velimir Matkovic, John Kissel, and colleagues at the Ohio State University Research Foundation are conducting the three-year study, now entering its second year.

CLINICAL CARE CONSIDERATIONS PROJECT

Clinical care considerations are standard guidelines that doctors and other caregivers use to design and implement a plan of care for patients.

MDA Medical Director and Vice President for Research Valerie Cwik has been part of a working group that includes experts from the Centers for Disease Control and Prevention and physicians at academic institutions in the United States and abroad, to develop a comprehensive set of clinical care considerations for the medical and psychosocial aspects of DMD. The target date for publication of this guideline is late 2008.

“The purpose of this important document is to promote more uniform care for those with DMD. It will impact the lives of tens of thousands individuals around the world who are living with this disease,” Cwik says.

HEALTHY HEARTS, HEALTHY LUNGS

Working with the American College of Chest Physicians and a group of pulmonologists with particular expertise in DMD, Cwik has co-authored a new consensus statement on the respiratory care and related management of DMD patients undergoing anesthesia or sedation.

MDA health care teams address all aspects of care during regular clinic visits.

The statement provides advice regarding the highly interrelated areas of respiratory, cardiac, gastrointestinal and anesthetic management of patients with DMD who are undergoing general anesthesia or procedural sedation. It offers an up-to-date summary of medical literature regarding this topic and identifies areas needing future research.

People with DMD who will be undergoing anesthesia or sedation should be sure their doctors know about these updated guidelines, published in the December 2007 issue of the journal Chest: www.chestjournal.org.

A separate set of cardiac care guidelines for individuals affected by DMD or BMD were published by the American Academy of Pediatrics in December 2005. These guidelines are available on the Web at: pediatrics.aappublications.org/cgi/content/full/116/6/1569.

General respiratory care guidelines are available at: ajrccm.atsjournals.org/cgi/content/full/170/4/456.

HOPE FOR TOMORROW — EXCITING RESEARCH STRATEGIES

Never before have so many different research fronts shown so much promise. Positive results are being seen in the areas of gene repair, gene replacement, stem cells and harnessing the body’s natural muscle builders.

RUNNING A STOP SIGN — PTC124

Dystrophin, like most genes, provides the blueprint for building a protein — in this case, a critical protein that gives skeletal muscles their strength and resilience. As genes go, dystrophin is gigantic. While the average human gene contains around 3,000 chemical “letters” of coding information, dystrophin’s 2.4 million letters make it the single-largest human gene.

And yet, a “typo” in just one of those 2.4 million letters can mean the difference between a gene that keeps muscles healthy and one that does not. One type of “spelling error” or mutation that occurs in about 15 percent of those with DMD mistakenly instructs skeletal muscles to stop building the dystrophin protein midway through the assembly line. Consequently, the unfinished protein can’t fulfill its crucial mission in muscle.

PTC124, a pill that may correct certain forms of DMD, has passed safety trials and now is in a larger trial to confirm its effectiveness.

Supported by a $1.5 million MDA grant, PTC Therapeutics may have found a way around this problem. The New Jersey pharmaceutical company has developed a revolutionary drug, called PTC124, a pill that orders muscle fibers to ignore these misplaced genetic “stop signs” (geneticists call them premature stop codons), enabling them to make functional dystrophin protein.

Preliminary studies have convinced scientists that PTC124 efficiently restores dystrophin production in human cells in the laboratory and in experimental mice whose dystrophin genes contain premature stop codons. Subsequent phase 1 clinical trials confirmed that healthy people tolerated the drug well.

Last October, PTC Therapeutics announced results from phase 2 clinical trials of PTC124 in boys whose DMD is due to a premature stop codon. In the laboratory, the researchers grew muscle cells sampled from 38 boys, and all 38 samples showed that PTC124 had stimulated the cells to produce normal dystrophin protein. Also encouraging, after taking the drug for 28 days, half the boys showed some evidence of dystrophin protein in muscle biopsies.

Blood levels of the muscle enzyme creatine kinase (CK), which are often markedly elevated in DMD, diminished in the boys after PTC124 treatment, offering evidence that the restored dystrophin protein could be helping to improve the boys’ muscle health. Even more heartening perhaps than the tangible scientific results, parents and teachers of several of the study participants noted the boys “had improvements in terms of greater activity level and increased endurance during the study duration.”

The first study of PTC124 in boys with DMD was undertaken primarily to determine (1) that the drug was safe over the short term in boys with DMD; and (2) whether or not dystrophin production was restored. The initial study was not designed to test whether the drug could preserve, or perhaps even improve, muscle strength and function. That is the purpose of the next study, already under way, which will be both larger (including some 165 boys) and longer (12 months of treatment).

For more information on this clinical trial and the eligibility criteria see: www.clinicaltrials.gov/ct2/show/NCT00592553?

MENDING BROKEN GENES — EXON-SKIPPING

MDA-supported scientists also are closing in on effective strategies for getting around other types of genetic errors besides premature stop codons. One approach that’s shown significant promise involves designer drugs that can coax the cellular gene-decoding machinery to simply “skip over” the part of the gene containing the error. You can envision the process as a sort of genetic copy-editing. Consider this sentence:

MDA’s teem of whirled-klass reaserchers, wercking rownd the klok, is searching for cures.

A nice sentiment, if you can get through all those mangled words. Instead of correcting every error, a ruthless editor might just slice out all the mistakes.

MDA is searching for cures.

Terse, perhaps, but it gets the message across.

A similar heavy-handed approach can work for dystrophin. Several research groups are designing drugs that can prompt muscle cells to skip over the error-containing segments (termed exons) of the dystrophin gene and stitch together the genetic instructions surrounding the mistake. The “patched” gene, while not as big as full-length dystrophin, can restore all or most of its protein-building instructions.

Prosensa, a Netherlands-based biopharmaceutical company, in collaboration with MDA-funded researchers, recently reported positive results from clinical trials of their exon-skipping drug, which target “exon-51,” a particularly error-prone region of the dystrophin gene. Similar versions of the drug could be tailored to skip over other faulty exons. Scientists say that targeting just 10 of the dystrophin gene’s 79 exons could potentially correct more than 85 percent of the mutations that cause DMD.

In these muscle biopsy photos, the green rings indicate dystrophin around muscle fibers. The muscles of a boy with DMD (upper left) have virtually no dystrophin, as compared to an unaffected individual (upper right). The bottom four photos show restored dystrophin in four boys treated with an exon-skippng drug.

The researchers reported that their drug was well-tolerated by the boys with DMD participating in the trial. Although this early trial was not designed to test whether the drug provides clinical benefits, muscle biopsies from the study participants revealed that they were producing significant amounts of dystrophin protein. MDA is following this and other exon-skipping studies very closely!

For further information on these and other clinical trials , visit www.clinicaltrials.gov/ct2/search, and type “Duchenne” or “Becker” into the search field.

A DASH OF GENES, A DOLLOP OF CELLS — GENE AND STEM CELL THERAPIES

In addition to developing ways to repair malfunctioning dystrophin genes, scientists have devised and are now refining methods to deliver fresh working versions of the gene to muscles.

One approach is to package dystrophin genes into non-harmful viruses that can “infect” muscles with their genetic cargo. Dystrophin’s monstrous size has proved a hurdle in these efforts. The gene is much bigger than most viruses can hold. Fortunately, scientists have learned that they can pare down the gene into “mini-dystrophin” genes that contain only the most essential parts. Jerry Mendell and his research team at Ohio State University recently obtained encouraging safety data on their phase 1 gene therapy project testing a mini-dystrophin gene in six participants. Mendell reports:

Dr. Jerry Mendell gives a hug to Julie Kilbarger, mother of the first boy to participate in a Phase 1 safety trial of gene therapy for DMD.

“The patients have been carefully followed for side effects of the treatment. None have been encountered. This is primarily a safety trial and we can confidently report that safety has been achieved. An additional goal is to lay the ground work for future gene therapy trials by establishing the ideal dose for treatment. In this trial, two doses have been tested and another will be required before completion of the study. We are recruiting three additional Duchenne muscular dystrophy patients to receive a higher dose that by all indications will be safe to administer. Upon completion of the 9 subjects we will be able to report to the scientific community and the public the results of the trial with recommendations for future gene therapy trials.”

For more information, see www.clinicaltrials.gov/ct2/show/NCT00428935?term=duchenne&rank=2.

You’ve probably read recent news reports about experiments with stem cells. Unlike mature “differentiated” cells, stem cells potentially can be coaxed to turn into virtually any other type of cell — including muscle-producing cells.

Wouldn’t it be wonderful if we could turn stem cells into healthy muscle cells and deliver them to people with muscular dystrophy? The trick, for researchers, is to decipher the developmental instructions that guide stem cells along their path toward becoming muscle.

Recently, researchers at the University of Texas Southwest Medical Center successfully turned mouse embryonic stem cells into muscle-producing cells and injected those cells into experimental mice that lacked dystrophin. The animals’ muscles suddenly produced dystrophin! The treated mice also showed dramatically improved muscle function. More experiments must be done before attempting this feat in humans, but the prospects are exciting indeed.

WORKING WITH UTROPHIN

Before birth, the muscles of developing babies contain a protein called utrophin, which looks and functions very much like dystrophin. Mysteriously, as babies mature, their utrophin becomes replaced with dystrophin in all but a very small part of their muscle fibers (the region around the neuromuscular junction where the nerves contact muscle fibers).

Several MDA-supported researchers are working intensely on learning how they might harness utrophin so that it can compensate for the dystrophin lacking in the muscle fibers of people with DMD. One way to do this would be through gene therapy.

Delivering extra utrophin gene copies to muscles, along with the genetic information necessary to turn on the genes in adult tissues, could be a more effective approach than gene therapy strategies employing dystrophin itself. Our body’s immune system can mount an attack against molecules it perceives as “foreign.” Those with Duchenne muscular dystrophy, whose bodies have never encountered dystrophin, might mount an immune response against the “foreign” dystrophin protein produced through gene or stem cell therapies. But since their bodies already make small amounts of utrophin, an immune response against new utrophin protein molecules would be very unlikely.

Researchers working with mice have successfully increased production of utrophin, a naturally occurring muscle protein that may substitute for dystrophin.

Instead of introducing new copies of the utrophin gene into the body, might it be possible to “negotiate” with the utrophin genes that are already there — perhaps coaxing them to churn out utrophin protein all around muscle fibers, rather than merely at the neuromuscular junction? In fact, scientists have achieved promising results with experiments aimed at accomplishing exactly that.

Last spring, MDA grantees Tejvir Khurana and Bernard Jasmin reported their discovery of a molecule in the body called ERF, that normally serves to turn down utrophin production in mature muscles. By reducing cellular ERF levels, the research team successfully increased utrophin production in both cultured muscle cells and experimental mice. The research teams of George Karpati and Josephine Nalbantoglu recently achieved similar results with a slightly different approach. These MDA-supported researchers designed artificial “gene switch” proteins that can supercharge the body’s utrophin gene so that it produces excess utrophin protein. When the scientists introduced the artificial switches into dystrophic mice, the animals’ muscles showed less degeneration and significant functional improvements.

“The approach, if further refined,” says Karpati, “may serve as a treatment for people with DMD.”

POISED FOR THE DAY

The recent explosive pace of experimental findings convinces all of us at MDA that we’re closer than ever to achieving effective treatments. But we’re not waiting around for breakthroughs. We are readying ourselves, our clinics, and — most importantly — our MDA families to take action the very day a treatment or cure is at hand.

MDA’S GENOTYPING CAMPAIGN

It’s clear that different people will need different types of therapy. Drugs that allow the body to read through premature stop-codons, for example, will not work for people without this type of mutation in their dystrophin gene. To direct patients to the most appropriate and potentially effective treatment strategy for their genetic make-up, we must know exactly what kind of mutation their dystrophin gene contains.

That’s why we’re launching an ambitious campaign to determine the dystrophin genotype — the letter-by-letter DNA sequence of the gene — for every person registered with MDA who has received a diagnosis of Duchenne or Becker muscular dystrophy.

In order to match individuals with DMD and BMD with the best potential treatment, MDA soon will launch a national genotyping campaign to identify each person’s exact genetic mutation.

The procedure itself will be easy — a simple blood draw. The magic begins from there. Using cutting-edge molecular biology and genomics technology, an MDA-contracted laboratory will purify the DNA contained in the blood sample and decipher the genetic code of the dystrophin gene. Of course, this will be done following strict patient privacy rules.

The information not only will benefit those with muscular dystrophy but will be a valuable resource for clinicians and researchers who may be able to uncover hidden patterns within the vast amounts of data. For example, similar types of mutations may be related to similar disease symptoms, progression and clinical outcomes that until now have eluded scientists. Stay tuned — we’ll have much more to tell you about this ground-breaking project as it takes shape.

(For the latest research updates, visit MDA’s “What’s New” section at www.mda.org.)

MDA CLINICAL RESEARCH NETWORK

MDA is investing a large amount of money and effort to build a clinical research network to study the disorders in the Association’s program, starting with DMD and ALS (or Lou Gehrig’s disease). At the start, we’ll select between five and 10 existing MDA clinics as clinical research centers, which will work together as an interactive network.

The network will test new treatments and conduct clinical studies aimed at enhancing and standardizing clinical care for DMD and ALS.

“With a number of potential therapies poised to move into clinical trials over the next several years, MDA clinics must be prepared to conduct these studies as efficiently as possible,” says Dr. Valerie Cwik, MDA medical director and vice president for research. “By funding the infrastructure necessary to conduct clinical studies and clinical trials, we hope to reduce or even eliminate some of the bottlenecks that commonly delay the start of such studies.”

EXPANDING THE CLINICAL TRIAL TENT

As experimental treatment evaluations move from animal to human studies, there’s an increased need for clinical trial participants. Unfortunately, clinical investigators currently aren’t prepared to open their studies to everybody. The problem is “clinical endpoints.”

Clinical endpoints are the results that scientists measure to judge the effectiveness of an experimental treatment. For instance, a measurement of muscle strength and the distance a person walks during a timed test are common clinical endpoints. While many clinical endpoints have been developed and validated for boys whose muscular dystrophy has not prevented their ability to walk, there’s not a standard set of validated clinical endpoints for nonambulatory patients.

MDA is working to fill that gap. This spring we will invite researchers to submit grant applications to develop and evaluate clinical endpoints for nonambulatory patients. This should benefit the whole DMD community, patients and researchers alike.

HELP AROUND THE GLOBE — MDA’S INTERNATIONAL COLLABORATIONS

MDA has joined forces with other health organizations around the world, with all eyes focused on one unifying goal: to end muscular dystrophy as soon as possible. By working together, MDA and its global partners aim to identify agendas of common interest, pool resources and expertise where appropriate, and examine the best ways to share knowledge and ideas to move the field of DMD research forward as quickly as possible.

The most immediate projects include:

• A clearinghouse to provide the DMD research and patient community with one central international repository for tracking research grants and key research resources.


• A global registry of patients, consolidated from scattered regional registries, which will enable health officials and researchers to study a much larger proportion of the world’s DMD cases.


• A professional ethics committee to advise industry and nonprofit organizations that support people with DMD.

MDA is collaborating with counterparts around the world to defeat DMD and BMD.

The mortar bonding many of these international initiatives is TREAT-NMD (Translational Research in Europe — Assessment and Treatment of Neuromuscular Diseases), a network of European agencies collaborating “to accelerate the progress of new cutting-edge therapies for neuromuscular diseases.”

Among the major TREAT-NMD projects underway are the formation of a global Clinical Trials Coordination Center and, in partnership with U.S. groups, the global patient registry.

Last November, MDA Medical and Science Editor Margaret Wahl, along with other representatives from Europe, North America, Australia and Japan, convened in Montpellier, France, to discuss contributing data to the TREAT-NMD patient registry.

To learn more, go to TREAT-NMD: www.treat-nmd.eu

DUCHENNE-BECKER ADVOCACY — REAUTHORIZING THE MD CARE ACT

Following landmark congressional hearings in December 2001 which included strong MDA representation and testimony from Jerry Lewis, Ed McMahon and former MDA National Goodwill Ambassador Benjamin Cumbo, the MD CARE Act was signed into law by President George W. Bush. The bipartisan Muscular Dystrophy Community Assistance, Research, and Education Act provided important authority and direction for muscular dystrophy research.

As a result of the MD CARE Act, important investments have been made by the federal government into muscular dystrophy research and research oversight. The MD CARE Act resulted in the formation of many important MD-centered research groups:

• MDCC (Muscular Dystrophy Coordinating Committee) This interagency coordinating council includes the National Institutes of Health (NIH) and scientific leaders from a number of organizations. Since the committee’s inception, MDA Vice President of Translational Research Sharon Hesterlee has served on the MDCC on behalf of the Association. The aims of the MDCC have been to expand, intensify and coordinate research activities related to muscular dystrophy.


• Six cooperative MD research centers, called the Wellstone Centers of Excellence, were funded as a result of the MD CARE Act:
• The University of Washington Seattle*
• The University of Rochester*
• The University of Pittsburgh*
• The University of Iowa, Iowa City
• Children’s National Medical Center, Washington, D.C.
• The University of Pennsylvania

*MDA provided $1.5 million dollars to each of the three original Wellstone Centers, supplementing the initial funding provided by the federal government.

The centers work individually and collaboratively, and are guided by the MDCC, which includes representatives from each center. Each has both basic and clinical research projects, and one or more core facilities to support them. Centers also must make core resources or services available to the national muscular dystrophy research community.

• The development of the MD STARnet (the MD Surveillance Tracking and Research Network). MD STARnet is a data collection and surveillance mechanism aimed at epidemiological research for MD. This project is being overseen by the Centers for Disease Control (CDC).

In order to ensure that the momentum created by the MD CARE act continues, MDA currently is working with others in the Duchenne community to revise, expand and reauthorize this important legislation.

In 2001, MDA National Chairman Jerry Lewis and former MDA Goodwill Ambassador Benjamin Cumbo helped convince Congress to pass the landmark MD CARE Act, which now is up for reauthorization.

Over the coming months, details about this legislative effort, and ways in which the MDA community can play a vital role in the passage of this legislation, will be made available through e-updates, the MDA Web site and Quest magazine.

To ensure that you’re able to receive timely updates about MDA’s advocacy efforts and DMD legislative ‘Calls To Action,’ please verify that your local MDA office has your most recent e-mail and mailing address.

To spearhead the MD CARE Act reauthorization effort, and monitor all matters affecting neuromuscular disease research and the care of individuals and families coping with muscle diseases, MDA recently named Annie Kennedy as vice president of advocacy. Having been with MDA for almost a decade, Kennedy has a long history of working on behalf of those with neuromuscular disease. And as a native of Washington, D.C., Annie feels right at home in the K Street office she now heads.

MDA’S RESEARCH PIPELINE

At MDA, the research pipeline never stops flowing. Our scientific, medical and translational research advisory committees meet every spring and fall to review a new round of grant applications and recommend the best proposals for approval by the MDA Board of Directors. Last fall alone, these committees recommended (and the Board approved) 54 new grants, totaling approximately $6 million of new funding in 2007. Most of these grants are renewable for up to three years. Here’s just a sampling of new grants in Duchenne/Becker muscular dystrophy that MDA is funding.

• DMD Therapy Through Utrophin Up-Regulation


• Skeletal Development in Boys with Duchenne Muscular Dystrophy


• Non-viral Gene Therapy for Duchenne Muscular Dystrophy Using phiC31 Integrase


• Stem Cells Prevent Duchenne Muscular Dystrophy in Mdx Mice


• Gene-Transfer-Based Follistatin Expression for Treatment of Muscular Dystrophy


• Antisense Mediated Suppression of DMD Frameshift Mutations


• Understanding Cardiac Dystrophin: Critical to Improving Gene Therapy for DMD


• Novel Designs and Outcome Measures for Bench to Bedside Research on DMD


• Auto-Cell Transplantation Therapy for Muscle Dystrophy Using Bone Marrow Stromal Cells