The researchers uncovered a novel mechanism that leads to motor neuron degeneration in spinal muscular atrophy (SMA). This discovery offers a new target for treatment that overcomes important limitations of gene therapy and other current therapies for SMA.
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.
The 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 the senior author. “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 the author.
Blocking Cdk5 activation alleviates symptoms in spinal muscular atrophy
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