New Theory to Treat SMA Tested in the Laboratory

A new approach to treating spinal muscular atrophy (SMA) is in the works in the laboratory of Matthew E. R. Butchbach at the Nemours Alfred I. duPont Hospital for Children in Wilmington, Delaware. The team of researchers, which includes Drs. Sean G. Mack, Daniel J. Cook, and Prasad Dhurjati, is sidestepping the fact that the gene SMN1 is missing in patients with SMA by using SMN2 to make the deficient protein SMN.

“This study shows how a systems biology approach can be used to develop potential therapeutic targets for treating SMA,” wrote the authors in their paper, “Systems Biology Investigation of cAMP Modulation to Increase SMN Levels for the Treatment of Spinal Muscular Atrophy,” published the journal PLOS One.

The team’s strategy is based on the fact that SMN2 can also produce functional SMN, albeit at a lower level than SMN1, and can partially compensate for the lack of SMN. By increasing the level of SMN2 expression, the researchers are hoping motor neuron cell death in the anterior horn of the spinal cord can be mitigated.

To begin testing their theory, the team exploited a region of the SMN2 gene that binds to cAMP, leading to SMN2 transcription. They treated fibroblasts, which were extracted from patients with SMA, with rolipram, salbutamol, dbcAMP, epinephrine, and forskolin, all of which are cAMP modulators. All molecules led to SMN protein within the nucleus of the fibroblasts, and protein levels were increased by an increasing treatment dose.

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Interested in further understanding the mechanism behind increased nuclear SMN, the team created two mathematical models to simulate SMN2 regulation by cAMP signaling. Parameters within both models led to results similar to those obtained by in vitro experimentation, indicating a great understanding of the mechanisms involved.

Using the generated model, the researchers tested two cAMP modulators simultaneously in silico. Concurrent treatment of SMA fibroblasts was predicted to additively increase SMN nuclear protein. “This study will also guide future investigations into the mechanisms by which cAMP signaling regulated SMN2 expression,” stated the authors, indicating that their model can be applied when exploring future treatments of SMA related to SMN2 expression.