Research Finds RNA Therapy Factors Ameliorate SMA Phenotype

In a recent study entitled “Spinal Muscular Atrophy Phenotype Is Ameliorated Either By SMN Increase Or Modulation Of Secondary Cell Death Events With RNA Therapy (S56.006),” a team of researchers from Milan, Italy, using a stem cell model sought to develop treatment approaches based on RNA for patients with Spinal Muscular Atrophy (SMA). The study was published in the journal Neurology.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder that causes loss of motor neurons and atrophy of the muscle, with patients presenting symptoms such as loss of strength in proximal muscles. Ultimately, SMA causes total paralysis and death. Mutations in the survival motor neuron gene (SMN1) are the cause of SMA. Currently, there is no available treatment, however, antisense therapy aiming at increase the SMN level is being studied as a treatment strategy.

Giulietta Riboldi and colleagues induced pluripotent stem cell (iPSC) lines in mice models derived from human skin fibroblasts. Then the researchers differentiated the iPSCs in order to stimulate motor neuronal phenotype. In the phenotype analysis, cells’ morphological, functional, gene expression, and protein examination were taken into account. Subsequently, they tested their proposed RNA strategy using antisense morpholino, ExSpeU1 and siRNA with the aim of increasing SMN levels or inhibiting Fas activation (Fas -ligand is a protein that regulates the immune system and the progression of cancer).

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Results from the analysis strongly suggested that iPSC-motor neurons were able to recapitulate the SMA phenotype. Furthermore, iPSC-motor neurons reduced the expression of the SMA phenotype from the mice that were under treatment with antisense morpholino or ExSpeU1. These features were able to restore SMN levels. Moreover,  SMA lines showed an increase in Fas ligand-mediated apoptosis.

Based on these results, researchers confirmed the value of SMA iPSCs-motor neurons with findings indicating that RNA treatment may be a feasible treatment strategy for patients with SMA. This procedure should additionally target the gene SMN up-regulation and modulation of disorder pathways.