Research Updates Fall 2011

Article Highlights:
by Quest Staff on October 1, 2011 - 10:09am

QUEST Vol. 18, No. 4
Featured in this update:

Families, experts meet at BMD Conference

Three trials study blood-vessel-dilating drugs in BMD, DMD

Results of daily, weekly prednisone treatment about the same in DMD

Eteplirsen being tested in walking boys with DMD

GSK2402968 being studied in nonwalking boys with DMD

Researchers studying DMD-affected families

Phase 3 trial of idebenone in DMD still open

Global registry established for people with LGMD, CMD due to FKRP mutations

FDA allows access to EPI-743 for some with FA, mitochondrial diseases

Dichlorphenamide is being tested in periodic paralysis

Periodic paralysis conference in Florida

Univ. of Florida site of gene therapy study in Pompe disease

Sodium phenylbutyrate studied in infants at risk of developing SMA

FDA OKs human testing of SMA drug RG3039

Treatment window for SMA may be wider than previously believed

Prolactin boosted SMN production in SMA mice, human cells

NIH studying exercise in men with SBMA

MDA awards $13.7 million in research grants


Families, experts meet at BMD Conference

Brian Tseng speaking at the BMD Conference
Brian Tseng, co-director of the MDA clinic at Massachusetts General Hospital in Boston, spoke about clinical care during the 2011 Becker Muscular Dystrophy Conference. (Photo by Thomas Neerken.)

People with Becker muscular dystrophy (BMD) were urged to learn their genetic mutation, participate in clinical trials and become advocates for themselves and their community at the third annual Becker Muscular Dystrophy Conference held Aug. 13, 2011, at Cedars-Sinai Medical Center in Los Angeles.

The gathering, which was sponsored by MDA, Cedars-Sinai and BeckerMD.org, brought together several hundred in-person and online attendees. Among them were people with BMD and their family members, as well as physicians, researchers, physical therapists and other experts. The conference was webcast and is slated to be available for viewing in November at http://blip.tv/beckermd.

Among the topics discussed were general clinical care, the heart in BMD, current research, stretching and exercise, and genetics. Participants learned about a clinical trial of tadalafil (Cialis) currently under way at Cedars-Sinai and were encouraged to enroll if eligible.

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Three trials study blood-vessel-dilating drugs in BMD, DMD

Trials are under way of the drugs tadalafil (Cialis) and sildenafil (Revatio, Viagra) in males with either Becker or Duchenne muscular dystrophy. Both drugs are part of a class of drugs called phosphodiesterase inhibitors and are known to dilate blood vessels, leading to increased blood flow. The drugs already are FDA-approved for treating erectile dysfunction.

At Cedars-Sinai Medical Center in Los Angeles, the effect of two consecutive doses of tadalafil on blood flow to the forearm muscles at rest and during handgrip exercise is being studied in men ages 18-55 with BMD. Principal investigator Ronald Victor has MDA support to conduct this trial. Because the specific action of tadalafil is to relax the muscles that line blood vessels, it is believed that the drug also may improve blood flow to skeletal muscles.

Contact Teresa Malott in Los Angeles at (310) 248-8080 or Julie Groth in Los Angeles at (310) 248-7641. For more information, visit ClinicalTrials.gov, and search for NCT01070511.

Also at Cedars-Sinai Medical Center, researchers are studying the effects of both tadalafil and sildenafil on blood flow to forearm muscles in boys ages 7-15 with DMD who are still walking and do not have signs of heart failure. It is believed that these drugs may improve blood flow to exercising muscles. Participants will be randomly assigned to one drug but will have the opportunity to switch to the other drug later in the study.

Contact Ashley Walker in Los Angeles at (310) 248-8080 or Julie Groth, also in Los Angeles, at (310) 248-7641. For more information, visit ClinicalTrials.gov, and search for NCT01359670.

Investigators at Kennedy Krieger Institute in Baltimore are studying the safety and effects on cardiac function of sildenafil in males ages 15-50 with BMD or DMD. In animal models of heart failure, inhibition of phosphodiesterase 5 led to favorable cardiac remodeling and improved blood-vessel tone.

Contact Genila Bibat in Baltimore at (443) 923-2778 or bibat@kennedykrieger.org. For more information, visit ClinicalTrials.gov, and search for NCT01168908.

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Results of daily, weekly prednisone treatment about the same in DMD

A yearlong, MDA-supported study comparing two prednisone dosing schedules in Duchenne muscular dystrophy (DMD) has found they have similar benefits and side effects.

Diana Escolar, formerly at Children’s Research Institute in Washington, D.C., received MDA support to direct this study, results of which were published online July 13, 2011, in Neurology.

Sixty-four boys with DMD who were 4-10 years old were randomly assigned to receive daily prednisone or a compressed, weekend-only prednisone dosing regimen for a year. Those in the daily group received the drug at 0.75 milligrams per kilogram of body weight per day. Those in the weekend-only group took 10 milligrams per kilogram of body weight of prednisone on Saturdays and Sundays only (one pound equals 0.45 kilograms).

Earlier results had suggested that weekend-only prednisone dosing might provide the same benefits with some reduction in side effects from this corticosteroid drug, but this full analysis of the results did not support these predictions.

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Eteplirsen being tested in walking boys with Duchenne MD

AVI BioPharma is testing its exon 51-skipping drug, eteplirsen (formerly called AVI-4658), in 12 boys with Duchenne muscular dystrophy (DMD) who are 7-13 years old, still walking, and have dystrophin gene mutations whose effects can potentially be lessened by skipping exon 51. The trial is being conducted at Nationwide Children’s Hospital in Columbus, Ohio.

AVI announced earlier this year that a trial of eteplirsen in DMD in the United Kingdom showed the drug resulted in production of dystrophin, the protein needed but missing in this disease. (See Research Updates, Quest, July 2011.)

The trial in Columbus is now fully enrolled. For details about this study, for which MDA is providing supplemental funding, go to clinicaltrials.gov and enter NCT01396239 in the search box. To see details of all trials of eteplirsen, visit ClinicalTrials.gov, and search for "eteplirsen."

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GSK2402968 being studied in nonwalking boys with Duchenne MD

GlaxoSmithKline is testing the safety and tolerability of its exon 51-skipping drug GSK2402968 at Nationwide Children’s Hospital in Columbus, Ohio, and in France, in 32 boys with Duchenne muscular dystrophy (DMD) who are at least 9 years old, no longer walking, and whose mutations lend themselves to skipping exon 51.

An earlier trial of GSK2402968 in Europe showed the drug resulted in dystrophin protein production and an increase in the distance participants could walk in six minutes, GSK announced in April 2011.

The Columbus study remains open to recruitment for people who meet study criteria and have out-of-frame deletions (see illustration, page 14) in the dystrophin gene in exons 13-50; 29-50; 43-50; 45-50; 47-50; 48-50; 49-50; 50; or 52.

Contact Xiomara Quintero Rosales in Columbus, Ohio, at (614) 722-6961 or Xiomara.Rosales-Quintero@nationwidechildrens.org. For details about this study, see the Center for Gene Therapy Clinical Studies at Nationwide Children’s Hospital, or enter NCT01128855 in the search box at ClinicalTrials.gov.

To see details of all studies of GSK2402968, enter this drug name into the search box at ClinicalTrials.gov.

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Researchers studying DMD-affected families

Genetic counseling student Belen Pappa is seeking participants for a survey-based study about psychosocial functioning in families in which a child has Duchenne muscular dystrophy (DMD). Pappa is in the Johns Hopkins University/National Human Genome Research Institute Genetic Counseling Training Program, which is jointly sponsored by Johns Hopkins and the National Institutes of Health.

The purpose of the study is to learn more about the relationship between how families function and how children adapt to having a sibling with DMD.

Pappa says that, while no direct benefits are expected from participation in the study, she hopes the information obtained will help professionals who interact with DMD-affected families.

She’s seeking parents of children with DMD who are living in the same home as their child; and sisters/brothers ages 13-18 also living in the same home as their sibling with DMD. Separate questionnaires for one parent and the sibling closest in age to the person with DMD are each estimated to take about 30 to 40 minutes to complete.

To receive the questionnaires and postage-paid return envelopes, contact Belen Pappa in Bethesda, Md., at (301) 443-1533 or pappamb@mail.nih.gov.

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Phase 3 trial of idebenone in Duchenne MD still open

A large-scale, phase 3 trial of idebenone (Catena) in boys with Duchenne muscular dystrophy (DMD) who are 10-18 years old remains open at one U.S. site and several sites in Europe, under the auspices of Santhera Pharmaceuticals. Prospective participants must meet all study criteria.

Catena, developed by Santhera, is designed to facilitate the transport of subatomic particles called electrons inside mitochondria, the energy-producing parts of cells. Results of a phase 2 trial of Catena, conducted in Belgium with 21 DMD-affected participants, suggest the drug is safe and well-tolerated at 450 milligrams per day for a year and that it may improve certain cardiac and respiratory measurements.

Those in the phase 3 trial are randomly assigned to receive 900 milligrams per day of Catena or a placebo for one year. The investigators are assessing pulmonary function, motor function, muscle strength and quality of life, as well as continuing to evaluate the safety and tolerability of this drug.

For information about the study at the U.S. site, contact Nancy Videon at Children’s Hospital of Philadelphia at (267) 426-7163 or videon@email.chop.edu. For details, visit ClinicalTrials.gov, and search for NCT01027884.

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Global registry established for people with LGMD, CMD due to FKRP mutations

A new registry has been launched for people with conditions caused by mutations in the gene for fukutin-related protein (FKRP). The registry is for people with the type 2I form of limb-girdle muscular dystrophy (LGMD2I) and the type 1C form of congenital muscular dystrophy (CMD1C) as well as FKRP-related forms of muscle-eye-brain disease and Walker-Warburg syndrome.

The online Global FKRP Patient Registry is designed to help researchers locate people with FKRP-related disorders who might be eligible to participate in future clinical trials of new therapies. It was developed by the TREAT-NMD Neuromuscular Network, an international network funded by the European Union that promotes research, therapy development and standards of care in neuromuscular diseases.

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FDA allows access to EPI-743 for some with FA, mitochondrial diseases

Edison Pharmaceuticals has gained the permission of the U.S. Food and Drug Administration (FDA) under an “expanded access” program to give EPI-743 to people with Friedreich’s ataxia (FA) or any of the mitochondrial myopathies in MDA’s program who are at least a year old and are judged to be within 90 days of end-of-life care.

EPI-743 is a small molecule whose proposed mode of action is regulation of energy metabolism in cellular structures called mitochondria. The study is based at Stanford University Medical Center and Lucile Packard Children’s Hospital in Stanford, Calif., with additional sites in Los Angeles and Orange, Calif.; New York; Akron, Ohio; Philadelphia; Charleston, S.C.; and Seattle and Bremerton, Wash.

Contact Katherine Connors in Stanford, Calif., at (650) 736-8166 or kconnors@stanford.edu. For more information, visit ClinicalTrials.gov and search for NCT01370447.

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About Clinical Trials

A clinical trial is a test, in humans, of an experimental treatment. Although it's possible that benefit may be derived from participating in a clinical trial, it's also possible that no benefit, or even harm, may occur. MDA has no ability to influence who is chosen to participate in a clinical trial.

To learn more, see Understanding Clinical Trials and Being a Co-Adventurer, which is about neuromuscular disease clinical trials.

Dichlorphenamide is being tested in periodic paralysis

A multicenter study of dichlorphenamide in 140 adults with hyperkalemic or hypokalemic periodic paralysis remains open at sites in California, Kansas, Massachusetts, Minnesota, Missouri, New York, Ohio and Texas, as well as in France, Italy and the United Kingdom.

The investigators will determine whether dichlorphenamide, when compared to a placebo, reduces the number of attacks of weakness or paralysis that people with periodic paralysis experience over the course of a nine-week period.

After the nine-week period, all participants will receive open-label dichlorphenamide for one year. The principal investigators are based at the University of Rochester (N.Y.), one of the study sites, and the trial is being sponsored by the U.S. National Institutes of Health.

Contact Patty Smith in Rochester, N.Y., at (585) 275-4339. For details and contact information for each study site, visit ClinicalTrials.gov and search for NCT00494507.

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Periodic paralysis conference Nov. 4-6 in Florida

The 2011 Periodic Paralysis Association Conference will be held Nov. 4-6 in Orlando, Fla. It’s geared toward people with periodic paralysis (PP), their families, physicians and friends. This is not an MDA-sponsored meeting, but several current and former MDA research grantees will be speaking.

The conference will be at the Rosen Centre Hotel in Orlando, which is offering a special room rate for participants. For reservations, call (888) 800-2174.

The meeting registration fee is $75 for adults and children 10 years and older. Children younger than 10 are free. (The Periodic Paralysis Association will try to help those for whom the expense is prohibitive.)

To register, contact Linda Feld in central Florida at (407) 339-9499. For details, see the conference website.

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University of Florida site of gene therapy study in Pompe disease

A six-person study of gene transfer in Pompe disease (acid maltase deficiency) using the gene for acid alpha-glucosidase (GAA, or acid maltase) is taking place at the University of Florida in Gainesville, with support from the National Heart, Lung and Blood Institute, a part of the National Institutes of Health (NIH).

Mutations in the GAA gene are the cause of Pompe disease. The study involves injections of functional versions of the GAA gene into the diaphragm muscle, with subsequent measurements of respiratory function. Participants must be 3-16 years old, use assisted ventilation, and meet other study criteria.

Contact Lee Ann Lawson in Gainesville, Fla., at (352) 575-0852 or llawson@pedcard.ufl.edu; or Lindsay Falk in Gainesville at (352) 273-9615 or lindsayc@peds.ufl.edu. For details, enter NCT00976352 into the search box at ClinicalTrials.gov.

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Sodium phenylbutyrate studied in infants at risk of developing SMA

A study of sodium phenylbutyrate in presymptomatic infants up to 3 months old whose genetic testing predicts they will develop type 1 spinal muscular atrophy (SMA1) will remain open to new participants through December 2011 at the University of Utah in Salt Lake City. The study also includes infants up to 6 months old whose genetic testing predicts they will develop type 2 SMA (SMA2) (that group is no longer open to new participants). In test tube and animal studies, sodium phenylbutyrate has been found to raise levels of the SMN protein, which is deficient in SMA.

MDA, the University of Utah and the National Institutes of Health are supporting this study. The investigators will assess the drug’s safety and tolerability and its effects on lean body mass and motor function. Contact Tara Newcomb in Salt Lake City at (801) 585-9717 or taran@genetics.utah.edu. For more information, visit ClinicalTrials.gov, and search for NCT00528268.

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FDA OKs human testing of SMA drug RG3039

The biotechnology company Repligen received approval in May 2011 from the U.S. Food and Drug Administration (FDA) to begin human testing of its experimental spinal muscular atrophy (SMA) drug RG3039. The drug is a small molecule designed to increase cellular levels of the SMN protein, which is deficient in SMA.

In June, the company announced that it had received FDA “fast-track” designation, which expedites the review of drugs that treat serious diseases and fill an unmet medical need. The first trial will test the drug in healthy human volunteers.

In December 2010, MDA awarded a $1.4 million grant to Repligen for development and testing of RG3039.

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Treatment window for SMA may be wider than previously believed

The “window of opportunity” for treating infants at risk of developing spinal muscular atrophy (SMA) may be weeks or months, not just days as some experts had feared, recent MDA-supported experiments in mice suggest.

MDA grantee Umrao Monani at Columbia University Medical Center coordinated the scientific team, which published its results Aug. 1, 2011, in the Journal of Clinical Investigation.

Monani’s group genetically engineered mice with an SMA-like disease caused by a deficiency of the SMN protein. Humans with SMA, like these SMA mice, lack SMN protein because of mutations in their SMN genes. The type of SMA mouse used in these experiments typically develops weakness on about the fourth day of life and generally lives about 17 days.

The researchers developed a system in which therapeutic genes for the SMN protein could be “turned on” in these mice at specific time points.

Mice in which SMN genes were activated on day 4 had a median survival time of 139 days. When researchers examined them between days 50 and 70, the animals looked the same as healthy mice except for having a lower body weight. Their grip strength, ability to stay on a rotating rod and other tests were equivalent to test results in healthy mice.

Inducing SMN protein production on day 6 or later, however, had a much more modest impact on survival and function, and no benefit was seen when mice were not treated until day 10.

Monani believes the day-4 to day-8 time period in mice probably corresponds to weeks to months after birth in humans.

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Prolactin boosted SMN production in SMA mice, human cells

The administration of a protein called prolactin slowed weight loss, improved motor function and increased life span by about 70 percent in mice with a disease resembling severe spinal muscular atrophy (SMA), researchers in Canada and Spain reported in July 2011.

Alex MacKenzie at the University of Ottawa, a former MDA grantee, and colleagues, found that mice injected with prolactin significantly increased their production of the SMN protein, which is deficient in SMA. They published their findings online July 25, 2011, in the Journal of Clinical Investigation. Human cells also showed increased production of SMN protein when treated with prolactin.

Further testing is needed to translate the prolactin findings from mice to humans. However, the study team suggested that prolactin’s SMN-elevating effects may prove even more powerful in humans than in mice, and they say the protein has the potential to benefit people who already have symptoms of SMA.

Prolactin also has been previously tested for its ability to help mothers of premature infants produce milk, and it’s been found to be safe in this context. Because it’s been tested in people, its development as a potential SMA therapy may move more quickly than that of a drug that hasn’t undergone previous human testing.

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NIH studying exercise in men with SBMA

A study of the safety and effectiveness of exercise in approximately 80 men with spinal-bulbar muscular atrophy (SBMA, or Kennedy disease) is under way at the National Institutes of Health (NIH) in Bethesda, Md. The utility of exercise in this disease is uncertain. The 16-week study requires two visits to Bethesda and monitoring at home. Participants must have genetically confirmed SBMA, be able to walk short distances, and meet other study criteria.

Contact Angela Kokkinis in Bethesda, Md., at (301) 451-8146 or akokkinis@cc.nih.gov; or Christopher Grunseich in Bethesda at (301) 435-9288 or christopher.grunseich@nih.gov. For more information, enter NCT01369901 in the search box at ClinicalTrials.gov.

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MDA Awards $13.7 Million in Research Grants

MDA has awarded 40 new research grants totaling $13.7 million to advance the understanding of disease processes and uncover new strategies for treatments and cures of muscular dystrophy and the more than 40 other diseases in the Association’s program.

The new grants were recommended by MDA’s Scientific and Medical Advisory Committees and approved by MDA’s Board of Directors at its July 2011 meeting.

New grants to established investigators and promising trainees

Of the 40 new grants, 33 are primary research grants, meant to improve understanding of the causes of neuromuscular diseases or guide the development of strategies for their diagnosis and treatment. These grants are given to established investigators.

In addition, seven awards are career development grants, designed to increase the number of outstanding scientists working on neuromuscular disease research. Awardees work in the laboratory of a senior investigator; each is given the flexibility to work independently or as part of a collaborative effort. (See Seeding the Field for more about MDA's grant programs.)

The 40 new awards will support research in 22 specific diseases in MDA’s program. In addition, several awards may apply to multiple diseases, because they support research on nerve or muscle physiology, nerve or muscle disease in general, muscular dystrophies in general or stem cells.

To see a slideshow about all the latest MDA-funded research projects, visit the MDA Research page and click on Grants at a Glance (left column).

To see all of the approximately 300 grants currently being funded by MDA, download MDA's list of Active Research Grants.

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