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 slideshow and links to individual grant descriptions (as well as to background materials) are included in the descriptions below
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.
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:
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.)
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:
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.
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.
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 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.
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.
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.
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.”