Making Connections: Research Deepens Understanding of Motor Neuron Disorders

Researchers at Nationwide Children’s Hospital are testing a groundbreaking therapy that could revolutionize the treatment of the largest genetic killer of infants. The clinical trial, launched in May, targets spinal muscular atrophy—or SMA—a genetic disease that attacks nerve cells called motor neurons in the spinal cord. There’s no current treatment for the childhood disorder beyond basic respiratory and palliative care, and 90 percent of infants with the most severe form of the disease, SMA Type 1, die within two years.

“There are numerous drugs in the pipeline for Motor Neuron Disorders, including some of our work that is being tested in the clinic, offering significant hope for this devastating disease,” says Brian Kaspar, PhD, of the Center for Gene Therapy at The Research Institute at Nationwide Children’s Hospital.

SMA, primarily an infant disease, occurs in an estimated one in 10,000 births. An abnormal or missing gene causes the disease, resulting in reduced production of a key protein called SMN (survival motor neuron). The malfunction can affect walking, crawling, breathing, swallowing and head and neck movements.

The experimental Nationwide Children’s Hospital therapy aims to replace the malfunctioning gene—called SMN1—with a healthy gene that’s injected into the bloodstream. Eligible for the trial are infants with SMA Type 1 younger than 9 months. “We’re hoping to actually stop the progression of the disease in patients who already have SMA,” says Dr. Kaspar, also an associate professor of pediatrics at Ohio State University.

Dr. Kaspar’s research has generated lots of excitement. The U.S. Food and Drug Administration has granted the gene therapy product “fast-track” and “orphan drug” designations after showing preliminary effectiveness in slowing the symptoms of SMA in mouse models. “We actually had the longest-surviving SMA mouse that’s ever been reported,” Dr. Kaspar says.

A previous breakthrough spawned the therapy. Dr. Kaspar and his team found a way to penetrate the blood-brain barrier, a protective network of blood vessels and cells that was an obstacle in previous gene therapies targeting SMA and ALS (Lou Gehrig’s Disease), another common motor neuron disease. They used a harmless virus to deliver the healthy gene across the barrier.

Dr. Kaspar also focuses on ALS in his research. Though it may seem unusual at first for a pediatric institution to conduct research related to ALS—primarily known as an adult disorder—Dr. Kaspar points out that scientists don’t actually know when the disease starts. Plus, a better genetic understanding of ALS could not only lead to quicker diagnoses and the removal of the mutation at an earlier age, but also could affect related illnesses. “Knowledge in any of these diseases would help us understand and potentially treat the other debilitating motor neuron diseases,” Dr. Kaspar says.

Indeed, Dr. Kaspar and his colleagues are experimenting with using the same delivery method used in the SMA clinical trial to reduce a toxic protein associated ALS. “We’ve had outstanding preclinical results that we’re excited to move forward into human trials as well, and working to garner the funding required to do so. We remain determined to make a difference for those with both SMA and ALS” he says.