Researcher Develops and Proves Effectiveness of New Drug for Spinal Muscular Atrophy

According to recent studies, approximately one out of every 40 individuals in the United States is a carrier of the gene responsible for spinal muscular atrophy (SMA), a neurodegenerative disease that causes muscles to weaken over time. Now, researchers at the University of Missouri have made a recent breakthrough with the development of a new compound found to be highly effective in animal models of the disease. In April, a patent was filed for the compound for use in SMA.

“The strategy our lab is using to fight SMA is to ‘repress the repressor,’” said Chris Lorson, a researcher in the Bond Life Sciences Center and professor in the MU Department of Veterinary Pathobiology. “It’s a lot like reading a book, but in this case, the final chapter of the book—or the final exon of the genetic sequence—is omitted. The exciting part is that the important chapter is still there—and can be tricked into being read correctly, if you know how. The new SMA therapeutic compound, an antisense oligonucleotide, repairs expression of the gene affected by the disease.”

In individuals affected by SMA, the spinal motor neuron-1 (SMN1) gene is mutated and lacks the ability to process a key protein that helps muscle neurons function. Muscles in the lower extremities are usually affected first, followed by muscles in the upper extremities, including areas around the neck and spine.

Fortunately, humans have a nearly identical copy gene called SMN2. Lorson’s drug targets that specific genetic sequence and allows proper “editing” of the SMN2 gene. The drug allows the SMN2 gene to bypass the defective gene and process the protein that helps the muscle neurons function.

Lorson’s breakthrough therapeutic compound was patented in April. His research found that the earlier the treatment can be administered in mice with SMA, the better the outcome. In mice studies, the drug improved the survival rate by 500 to 700 percent, with a 90 percent improvement demonstrated in severe SMA cases, according to the study.

Although there is no cure for SMA currently, the National Institutes of Health (NIH) has listed SMA as the neurological disease closest to finding a cure, due in part to effective drugs like the one developed in Lorson’s lab.

Researcher Advancing Motor Neuron Studies

Supported by the commitment of the University of Connecticut and the state to stem cell research, a UConn Health Center researcher is advancing the understanding of the devastating inherited condition known as spinal muscular atrophy.

Xue-Jun Li, assistant professor in the Department of Neuroscience, is corresponding author of a paper published in the prestigious journal Cell Research in December 2012 entitled “Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy.” The paper’s other authors are UConn Health Center researcher Zhi-Bo Wang and Xiaoqing Zhang of the Tongji University School of Medicine in Shanghai.

Spinal muscular atrophy (SMA) is a group of inherited diseases that cause muscle damage and debilitation, which progress over time and eventually lead to death. To be affected, a person must inherit the defective gene from both parents. About 1 in 10,000 people have SMA, and most do not survive childhood due to respiratory problems, heart failure and infections.

“There is no effective treatment for spinal muscular atrophy, and one of the roadblocks is not knowing why the spinal motor neuron degenerates,” Li explains. “One of the aspects of our research is to understand how specific types of neurons are specified and degenerated. We are trying to model neurological disorders by using human motor neurons derived from stem cells.”

Establishing human cell models of SMA to mimic motor neuron-specific phenotypes holds the key to understanding this destructive disease, she says. The model described in the journal article provides a unique paradigm for studying how motor neurons degenerate. It also highlights the potential importance of antioxidants for the treatment of SMA.

Understanding how motor neurons are specifically degenerated can lead to effective interventions in the future. “It can help us find some way to rescue the motor neuron degeneration in this disease,” Li points out. “Understanding the role of antioxidants can provide potential clues to finding a treatment.”

Mechanisms Underlying Childhood Neuromuscular Disease Found

A study by scientists from the Motor Neuron Center at Columbia University Medical Center (CUMC) suggests that spinal muscular atrophy (SMA), a genetic neuromuscular disease in infants and children, results primarily from motor circuit dysfunction, not motor neuron or muscle cell dysfunction, as is commonly thought. In a second study, the researchers identified the molecular pathway in SMA that leads to problems with motor function. Findings from the studies, conducted in fruit fly, zebrafish and mouse models of SMA, could lead to therapies for this debilitating and often fatal neuromuscular disease. Both studies were published today in the online edition of the journal Cell (1, 2).

“Scientists call SMA a motor neuron disease, and there is post-mortem evidence that it does cause motor neurons to die,” said Brian McCabe, PhD, assistant professor of pathology and cell biology and of neuroscience in the Motor Neuron Center, who led the first study. “However, it was not clear whether the death of motor neurons is a cause of the disease or an effect. Our findings in the fruit fly SMA model show that the disease originates in other motor circuit neurons, which then causes motor neurons to malfunction.”

In motor circuits, which coordinate muscle movement, specialized sensory neurons called proprioceptive neurons pick up and relay information to the spinal cord and brain about the body’s position in space. The central nervous system then processes and relays the signals, including via interneurons, to motor neurons, which in turn stimulate muscle movement.

“To our knowledge, this is the first clear demonstration in a model organism that defects in the function of a neuronal circuit are the cause of a neurological disease,” added Dr. McCabe.