Scientists from the Ottawa Hospital Research Institute (OHRI) and the University of Ottawa have identified a promising new approach for developing drugs to treat Spinal muscular atrophy (SMA), the leading inherited cause of death in infants and toddlers. Dr. Rashmi Kothary and his doctoral student Melissa Bowerman have found that an enzyme called RhoA is overly active in a mouse model of the disease and blocking this enzyme can greatly increase survival. The study is published in Human Molecular Genetics.
The research began as an attempt to understand the molecular pathways that are involved in SMA. Scientists have known for many years that this disease is caused by inherited mutations in a gene called survival motor neuron 1 (SMN1). These mutations cause nerve cells to lose their ability to control muscles, but researchers have never fully understood why. Several years ago, Dr. Kothary's team developed a model of SMA using nerve-like cells in the laboratory. They showed that the internal scaffold that gives these cells their shape was defective, and enzymes involved in maintaining the scaffold, such as RhoA, were not being regulated properly.
In the current study, Dr. Kothary's team investigated a compound called Y-27632, which is known to block the RhoA pathway. The compound was developed by other researchers more than 20 years ago and it has been used extensively in laboratory studies, although it has never been tested in humans. Mice with a version of SMA were treated with a high dose of Y-27632, a low dose or a placebo. The mice with the high dose survived significantly longer, well into adulthood. By comparison, the other mice survived only to about four weeks. This is the greatest increase in survival ever demonstrated in this model of SMA, although the compound was still not able to fully restore lifespan or correct all the nerve problems associated with the disease.