IDENTIFICATION OF NOVEL SMN-INDEPENDENT SMALL MOLECULES FOR SPINAL MUSCULAR ATROPHY THROUGH DRUG REPOSITIONING

Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by lower motor neuron (MN) degeneration and muscle atrophy, caused by mutations in the Survival of Motor Neuron 1 (SMN1) gene. Although three SMN-dependent therapies are currently available and highly effective, especially when administered early, relevant limitations remain, highlighting the need for alternative or synergistic therapeutic strategies. In this context, drug repositioning (DR) represents a promising approach to identify novel treatments, while reducing development time and costs.
Here, we investigated 10H-phenothiazine (10H-PTZ), a neuroprotective small molecule targeting mechanisms similarly altered in Parkinson’s disease, Alzheimer’s disease, and SMA. We first validated primary cortical neurons derived from SMNΔ7 mice as a reliable in vitro SMA model for drug screening, as they recapitulate key SMA-related defects in neuronal viability and morphology. Treatment with 10H-PTZ (10 nM) significantly improved neuronal survival and morphology, including soma area, neurite length, and branching. These protective effects were further confirmed in vivo using a C. elegans SMA model, where 10H-PTZ treatment resulted in a significantly increased number of viable MNs.
In parallel, we are performing high-content DR screening in the C. elegans SMA model to identify additional FDA-approved compounds to be validated in our in vitro models. Preliminary data indicate improvements in neuronal viability, morphology, synaptic vesicle distribution, and modulation of mitochondrial activity and cytoskeletal protein expression. Moreover, first in vivo analyses are ongoing.
Overall, our findings support drug repositioning as a valuable strategy to identify novel neuroprotective compounds, expanding therapeutic opportunities for SMA.