Spinal Muscular Atrophy

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

Research Projects

Abnormal fatty acid metabolism is a core component of spinal muscular atrophy
26/07/2019

We identify an increased susceptibility to developing dyslipidemia in a cohort of 72 SMA patients and liver steatosis in pathological samples. Similarly, fatty acid metabolic abnormalities were present in all SMA mouse models studied.
Targeted Ablation of the Cellular Inhibitor of Apoptosis 1 (cIAP1) Attenuates Denervation-Induced Skeletal Muscle Atrophy
03/05/2019

Skeletal muscle atrophy is a pathological condition that contributes to morbidity in a variety of conditions including denervation, cachexia, and aging. These results demonstrate the cIAP1 is an important mediator of NF-κB/MuRF1 signaling in skeletal muscle atrophy and is a promising therapeutic target for muscle wasting diseases.
Recessive mutations in ATP8A2 cause severe hypotonia, cognitive impairment, hyperkinetic movement disorders and progressive optic atrophy
03/05/2019

ATP8A2 gene mutations have emerged as the cause of a novel neurological phenotype characterized by global developmental delays, severe hypotonia and hyperkinetic movement disorders, the latter being an important distinguishing feature.
Evidence for Clinical, Genetic and Biochemical Variability in Spinal Muscular Atrophy With Progressive Myoclonic Epilepsy
01/12/2014

The results of the WES and the functional studies prompted an electromyography (EMG) study that showed evidence of motor neuron disease despite only mild proximal muscle weakness.