Story includes research items about: limb-girdle and Duchenne muscular dystrophies, myasthenia gravis, mitochondrial myopathy, Friedreich's ataxia, spinal muscular atrophy
Experiments conducted in mice suggest gene therapy for type 2D limb-girdle muscular dystrophy (LGMD2D)has the potential to be safe and effective in humans with this serious muscle disease, says an MDA-supported study.
|Longtime MDA grantee Jerry Mendell at Ohio State University coordinated the LGMD2D gene transfer study in mice and is also overseeing a human LGMD2D gene transfer trial.|
Longtime MDA grantee, neurologist and clinical gene therapy specialist Jerry Mendell of Ohio State University and Nationwide Children’s Hospital in Columbus, coordinated the research team, which included investigators from those institutions and from Harvard Medical School in Boston. Mendell is also overseeing a clinical trial at Nationwide to evaluate the safety of gene transfer in six people with LGMD2D. (See “Gene transfer trial.”)
The investigators, who published their findings July 22 in Neurology, transferred human genes for the alpha-sarcoglycan protein, which is deficient in the muscles of people with LGMD2D, into mice that dont produce this muscle protein.
In contrast to a study published in 2002 that suggested overproduction of alpha-sarcoglycan could have toxic effects in muscle tissue, this new study found intramuscular injections of the alpha-sarcoglycan gene to be safe and effective in the mice.
The authors note that the difference in their results compared to the 2002 study could be related to differences in the gene delivery vehicles, the methods used to purify them or other factors.
They also say, however, that mouse studies can only go so far in answering questions about safety and efficacy for gene therapy in humans and that better understanding of these outcomes awaits the results of the clinical trial.
|Jeffrey Chamberlain, an MDA grantee at the University of Washington-Seattle, coordinated the utrophin gene transfer research group.|
A research team coordinated by MDA grantee Jeffrey Chamberlain at the University of Washington-Seattle found intravascular gene transfer with a miniaturized utrophin gene had roughly the same benefits as intravascular gene transfer with a miniaturized dystrophin gene, in mice missing both utrophin and dystrophin and showing a severe disease resembling Duchenne muscular dystrophy (DMD). The team published its results in the September issue of Molecular Therapy.
Like dystrophin, the protein missing in boys with DMD, utrophin is a muscle protein. But unlike dystrophin, utrophin is produced by boys with DMD. The protein’s similarity to dystrophin has prompted researchers to experiment with its ability to compensate for missing dystrophin. The advantage of using utrophin instead of dystrophin for gene transfer in DMD is that patients’ immune systems are used to “seeing” it and are unlikely to reject it as foreign protein.
In a mouse model of a mitochondrial myopathy, (a muscle disease involving defects in the cellular “energy factories” known as mitochondria), increasing the number of functional mitochondria improved symptoms and prolonged life, say researchers at the University of Miami.
The investigators, including MDA-supported Carlos T. Moraes and Francisca Diaz, published their findings in the Sept. 3 issue of Cell Metabolism.
In one set of experiments, the investigators developed mice with extra genes for PGC-1-alpha, a metabolism regulator that increases production of mitochondria. In a second set, they gave the mice the drug bezafibrate, which stimulates PGC-1-alpha activity. With both approaches, the mice experienced milder disease symptoms with later onset and longer life spans.
The findings offer a new avenue for research aimed at treating mitochondrial diseases.
|Destruction of acetylcholine receptors at neuromuscular junctions is a major cause of myasthenia gravis, but interference with the MuSK enzyme can also cause the disease.|
Immune-system proteins called antibodies that stick to and destroy an enzyme known as muscle-specific kinase (MuSK) have been identified beyond a reasonable doubt as the cause of myasthenia gravis (MG)in about 10 percent of people with MG.
MDA grantee William Phillips at the University of Sydney (Australia) coordinated a team of researchers at his institution and at Concord (Australia) Hospital to investigate the mechanism by which anti-MuSK antibodies cause MG, publishing results in the June issue of Annals of Neurology.
Since the 1970s, it’s been known that a major cause of MG are antibodies that can destroy acetylcholinereceptors, which are molecular “landing pads” on muscle cells that receive signals from nerve cells. Without adequate numbers of these receptors, signals can’t jump from nerve to muscle, and severe weakness results.
Antibodies are a normal part of the immune system’s defenses against bacteria, viruses and other threats to an organism’s well-being, but when they attack normal tissue, the result is an autoimmune (self-immune) disease, such as MG.
Some patients with autoimmune MG don’t have anti-acetylcholine receptor antibodies, but have antibodies to MuSK, an enzyme important for maintaining the neuromuscular junction, the place where nerve and muscle cells interact and where the acetylcholine receptors are located.
Phillips and co-workers have shown that, when anti-MuSK antibodies from patients with symptoms of MG but no anti-acetylcholine receptor antibodies are injected into healthy mice daily for two weeks, the mice develop an MG-like disease.
When examined microscopically, the neuromuscular junctions of the MuSK antibody-treated mice showed far fewer acetylcholine receptors and an abnormally long distance between the nerve-cell fibers and the receptors.
The scientists say they’ve shown that transfer of human anti-MuSK antibodies to mice results in an MGlike disease and that MG patients who have anti-MuSK antibodies can be certain these are the cause of their disease.
Together with work by others, these experiments provide evidence that MuSK is needed to maintain the health of the neuromuscular junctions, and suggest that boosting the MuSK signal may, in the long term, be another approach to treating MG.
|In Friedreich’s ataxia, a deficiency of the frataxin protein changes the way the body regulates iron levels, leading to toxic levels of iron in the cellular mitochondria. Chelators designed to penetrate the mitochondria target the iron accumulation and reduce it.|
Experiments examining the effects of iron “chelation,” a process that removes toxic levels of iron from cells, have provided insight to the potential therapeutic value of the process in Friedreich’s ataxia (FA).
A deficiency of the frataxin protein, the underlying cause of FA, changes the way the body regulates iron levels and leads to toxic levels of iron in the cellular “energy factories” known as mitochondria. The disease damages the heart and nervous system.
Iron chelation limits the harmful increase in cell size in the muscle tissue of the heart (“myocardial hypertrophy”) in mice with a disease that closely mimics FA, say researchers at the University of Sydney, New South Wales, Australia.
The investigators, who also added to the understanding of FA at the molecular level, published their findings in the July 15 issue of Proceedings of the National Academy of Sciences. MDA supported Des Richardson at the University of Sydney for this work.
Starting at age 4.5 weeks, before disease effects were present, and continuing until they reached 8.5 weeks and had pronounced symptoms, the FA mice received iron chelation therapy five days a week with a compound that penetrates mitochondria. The chelation-treated mice showed a marked and significant decrease in cardiac iron levels compared to those treated with a placebo.
The investigators note that, although chelation reduced iron levels and limited cardiac hypertrophy in the FA mice, the animals still had decreased cardiac function as well as the weight loss and hunched stance typical of those with the FA-like defect.
Importantly, however, the chelation didn’t lead to overall body iron depletion in the mouse, or toxicity, making it a potential therapeutic strategy for the disease.
The study results are “very important in understanding and treatment of the highly aggressive neurodegenerative and cardiodegenerative disease Friedreich’s ataxia,” said Richardson.
“We’ve demonstrated for the first time the processes responsible for the iron loading that underlies Friedreich’s ataxia and uncovered a possible treatment strategy to target the toxic iron accumulation and remove it.”
Spinal muscular atrophy (SMA), long believed to be caused by the loss of motor neurons (nerve cells that control muscle) in the spinal cord, may begin with events preceding motor neuron loss, according to a group of researchers coordinated by MDA grantee Umrao Monani at Columbia University in New York.
Monani and colleagues, who published their results Aug. 15 in Human Molecular Genetics, say the findings could have important implications for development of SMA treatments.
The underlying cause of SMA is a deficiency of the SMN (survival of motor neuron) protein. The more SMN one has, the better, with very low levels resulting in severe disease and somewhat higher levels resulting in less severe disease. Until recently, the steps between SMN depletion and loss of motor neurons were obscure.
The new findings point to the meeting place of nerve and muscle fibers — the neuromuscular junction — as the first casualty in SMA, with the loss of motor neuron cell bodies coming as a later event. (Motor neurons have cell bodies in the spinal cord and long, thin fibers called axons that travel outside the cord and activate muscle fibers by sending them chemical signals.)
Working with SMA mice with varying levels of SMN and disease of varying severity, the researchers found the first detectable signs of SMA to be abnormalities at the tip of the axon as it nears the muscle fiber. In the SMA mice, clumps of cellular material accumulated in these axon tips on the nerve side of the neuromuscular junction. On the muscle side, the receptors (receivers) of the nerve signals formed abnormal clusters and didn’t mature properly. The extent and severity of these defects correlated with disease severity and with SMN levels.
An analysis of diaphragm muscle tissue taken from severely affected SMA patients revealed neuromuscular junction defects similar to those seen in the SMA mice.
The researchers say their findings “warrant the search for strategies that would maintain function at the neuromuscular junctions as a means of treating the disease.”