In this issue: An MDA-supported gene therapy safety trial gets federal approval to move forward ** Sudden cardiac death found in people with MMD2, and those with MMD1 often require a pacemaker ** Etanercept shows promise in mysasthenia gravis
|R. Jude Samulski|
The Recombinant DNA Advisory Committee (RAC), part of the National Institutes of Health (NIH) in Bethesda, Md., voted on Dec. 16 that an MDA-supported gene therapy safety trial — the first such trial in boys with Duchenne muscular dystrophy (DMD) in the United States — can move forward. Next steps include further animal safety testing and approval by the U.S. Food and Drug Administration (FDA).
The study, once approved, will be conducted by neurologist Jerry Mendell of Columbus Children’s Research Institute, part of Ohio State University; R. Jude Samulski, a virus specialist at the University of North Carolina in Chapel Hill; and Xiao Xiao, a molecular biologist at the University of Pittsburgh. Samulski and Xiao are part of Asklepios Biopharmaceutical, a biotechnology company in Chapel Hill.
The investigators plan to test the safety of a laboratory-engineered gene for the muscle protein dystrophin, tucked inside a modified adeno-associated virus (AAV). (See “Bridge Over Troubled Waters,” January-February.)
If all goes according to plan, six boys with DMD who are at least 10 years old will receive injections of the AAV-encapsulated genes into one biceps muscle, while the opposite biceps receives placebo (sham) injections.
After about six weeks, samples of the muscles will be examined for evidence of dystrophin production and signs of damaging reactions, such as an unwanted immune response. The participants will undergo many other types of safety testing during and after the injections.
The trial isn’t seeking participants at this time.
In a study of type 2 myotonic dystrophy (MMD2), sudden death from cardiac causes occurred in four people, three of whom had no prior symptoms, report researchers at the University of Minnesota in Minneapolis and several centers in Germany.
The investigational team included MDA research grantees Laura Ranum and John Day at the University of Minnesota-Twin Cities. Day also directs the MDA clinic at Fairview-University Medical Center in Minneapolis.
The researchers studied medical records and other data from 297 people with genetically confirmed MMD2.
The four who died had the “dilated” type of cardiomyopathy, and two of them also had scarring of heart cells that conduct signals through the tissue.
In their report in the Dec. 28 issue of Neurology, the authors write, “Our observations reveal that DM2 [type 2 MMD] patients are at risk for severe cardiac complications that need close cardiac surveillance.”
While the cardiac problems associated with type 1 MMD have been the subject of much study in recent years (see "Heart Problems," below), the extent to which MMD2 is associated with these problems has only recently become clear.
“These findings substantiate the need for patients with both types of MMD to have frequent clinical evaluations to assess heart function,” Day said.
Last year, researchers at the University of Wurzburg in Germany found that people with MMD2 can have subtle heart problems long before they develop symptoms and that older MMD2 patients can develop cardiomyopathy, a degeneration of cardiac muscle cells (see “Clinical Trials and Studies,” January-February 2005).
A ongoing study of heart problems in type 1 myotonic dystrophy (MMD1) that began in 1997 has released two sets of interim results.
The study is being conducted under the direction of cardiologist William Groh at the Krannert Institute of Cardiology of Indiana University in Indianapolis and has had support from medical electronics manufacturer Medtronic and from MDA.
As of June, 440 patients were enrolled in the study. In a subsection, six people had a device implanted underneath the skin of the chest to constantly record heart rate and rhythm. Serious problems were detected in three people, and two received an electronic device to correct problems.
As of January, 57 participants (13 percent of the 440) were noted to have entered the study with a diagnosed heart problem. At study entry, nine of them (2 percent) had a pacemaker. By January, 37 (9 percent) had had a pacemaker inserted.
Residents of the Indianapolis area who believe they have MMD1 are still being enrolled. Contact clinical research coordinator Miriam Lowe at (317) 962-0080, (800) 843-2786 or firstname.lastname@example.org.
Doctors at the University of Illinois and Rush University Medical Center in Chicago and the University of Texas at Galveston have found that the drug etanercept (Enbrel) may offer hope to some people with myasthenia gravis (MG) who need relatively high doses of corticosteroids, such as prednisone.
In the autoimmune disease MG, the immune system mistakenly attacks the part of the muscle cell that receives signals from a nerve cell, leading to fluctuating weakness.
Etanercept, which has FDA approval for the treatment of arthritis and psoriasis, blocks the action of tumor necrosis factor (TNF), a substance secreted by cells of the immune system that has been implicated as a contributor to MG.
The doctors originally enrolled 11 people with MG, all of whom had needed at least 25 milligrams of prednisone every other day for more than six months to control symptoms. This is a potentially toxic corticosteroid level.
Six of the 11 patients improved with etanercept, administered by injection twice a week, based on measures of muscle strength and the ability to successfully taper their prednisone doses. Two others withdrew when their disease worsened.
The study team, which included MDA grantees Erdem Tuzun and Premkumar Christadoss at the University of Texas at Galveston, published its findings in the Dec. 28 issue of Neurology. (Amgen, which markets Enbrel, contributed to funding for the trial.)