A transcriptomics based drug repositioning approach to identify drugs with similar activities for the treatment of muscle pathologies in spinal muscular atrophy (SMA) mice.
Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder characterized by motor neuron loss and progressive muscle atrophy and weakness. Predominantly, SMA is caused by loss of function of the survival of motor neuron 1 (SMN1) gene leading to a reduction of SMN protein levels. Although three therapies that boost SMN levels in SMA patients are clinically approved and are successful in slowing down disease progression, they do not completely reverse the disease phenotype in key tissues such as neurons and skeletal muscle. Thus, complementary SMN-independent therapies that target SMA pathologies are required to bolster improvements in SMA. Our project focused on using drug repositioning, as previously we have demonstrated that prednisolone, a synthetic glucocorticoid (GC) improved muscle health and survival in both severe Smn-/-;SMN2 and intermediate Smn2B/- SMA mouse models. However, due to the adverse risks from long term GC administration, we wanted to identify clinically approved drug candidates that are predicted to emulate prednisolone's beneficial effects in SMA muscle. Therefore, we ran an RNA-sequencing, transcriptomics and drug database pipeline on triceps from post natal day (P)7 symptomatic, prednisolone treated (5 mg/kg, every other day from P0) and untreated severe Smn-/-;SMN2 and healthy Smn+/-;SMN2 mice. Using this, we were able to identify molecular targets linked to prednisolone's ameliorative effects in SMA muscle and use them to predict clinically approved drug candidates for pre-clinical studies in SMA cellular and animal models.