New target found for treatment of spinal muscular atrophy

SMA is a genetic disease that disrupts the nerve cells that control voluntary muscle movement. Symptoms of motor neuron degeneration could start at as early as 3 months of age and lead to muscle atrophy, paralysis and death, often before the child's second birthday. Gene therapy has revolutionized SMA treatment, but it only works for a subgroup of patients and it can be too toxic.

Dr. Ma and team found that in SMA, increased activity of a type of enzyme called cyclin-dependent kinase 5 (Cdk5) causes defective function of mitochondria, which is a powerhouse of the cell and serves as a signaling center for many cell processes. In SMA, the mitochondrial dysfunction contributes to cell death or degeneration of motor neurons, and this occurs before symptoms develop.

The researchers also demonstrated in mouse models and human induced pluripotent stem cell (iPSC) models of SMA that the mitochondrial dysfunction and motor neuron degeneration can be stopped by a Cdk5 inhibitor. After reducing Cdk5 activity, the mice showed significant improvement in SMA symptoms. Findings were published in the Proceedings of the National Academy of Sciences (PNAS).

"We are excited to offer promise of a brand new treatment for children with SMA," said senior author Dr. Ma, who holds the Children's Research Fund Endowed Professorship in Neurobiology at Lurie Children's and is Associate Professor of Pediatrics, Neurology, and Neuroscience at Northwestern University Feinberg School of Medicine. "In our previous research, we established that all patients with SMA have the mitochondrial defect. This means that inhibiting Cdk5 could treat all patients, including children whose SMA subtype makes them ineligible for gene therapy. This new approach also could potentially be used in combination with gene therapy. The currently available Cdk5 inhibitor is too toxic, so we want to develop a better inhibitor that is safer and more effective."

Once a better inhibitor is developed, treatment could start as soon as SMA is diagnosed through newborn screening, before symptoms appear, explains Dr. Ma.

The study was supported by National Institutes of Health grants R01NS094564, R21NS106307, and RF1AG077451, as well as grants from the Hartwell Foundation, Cure SMA, and the Agape Foundation.

Research at Ann & Robert H. Lurie Children's Hospital of Chicago is conducted through Stanley Manne Children's Research Institute, which is focused on improving child health, transforming pediatric medicine and ensuring healthier futures through the relentless pursuit of knowledge. Lurie Children's is a nonprofit organization committed to providing access to exceptional care for every child. It is ranked as one of the nation's top children's hospitals by U.S. News & World Report. Lurie Children's is the pediatric training ground for Northwestern University Feinberg School of Medicine.