In Spinal Muscular Atrophy or SMA, motor neurons (the nerve cells which carry impulses from the brain and spinal cord to our muscular system) die off resulting in generalized weakness and respiratory failure. SMA is one of the most common inherited causes of infant death with an incidence of 1 in 10,000 live births. Although a gene called SMN1 is usually deleted in SMA, there is a second almost identical gene SMN2 is present in all infants with SMA. This gene makes lower levels of the protein which when missing causes SMA; the ability to turn up this second gene to make more of the missing protein has become a goal of our and a number of other labs.
At CHEO, we have identified small clinic ready compounds which we have shown to produce more functional protein in nerve cell culture and in mice with SMA. We are proposing of testing one of the FDA approved drug celecoxib for human clinical trials. We have already received approval from Health Canada for the trials. The proposed clinical trial will assess whether celecoxib treatment increases SMN protein levels in patient leukocytes along with finding the optimal dose of celecoxib for future efficacy trials.
Our researchers are currently also investigating whether the primary function of SMN protein within motor neurons is to transport axonal and pre-synaptic transcripts (especially β-actin) to the growth cones for the preservation of mature and functional neuromuscular junctions architecture. This study will validate SMA pathophysiologic model and will also help in the development of novel SMN independent therapeutic strategies for the treatment of SMA