# Validation in Drosophila of the in silico predicted clomipramine as repurposable for SOD1-ALS

## TL;DR

This study validates clomipramine as a potential treatment for SOD1-related ALS using fruit fly models, showing improved lifespan and reduced disease markers.

## Contribution

The novel contribution is the experimental validation of in silico drug repurposing predictions in a Drosophila model of SOD1-ALS.

## Key findings

- Clomipramine improved lifespan and climbing abilities in Drosophila SOD1-ALS models.
- The drug mitigated genomic instability and inflammation in these models.
- Clomipramine outperformed other tested compounds like mianserin and modafinil.

## Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive motor neuron degeneration and muscle weakness, generally leading to death due to respiratory failure within 2–5 years of symptom onset. Current Food and Drug Administration-approved drugs —riluzole, edaravone, and tofersen — offer limited clinical benefit due to ALS multifactorial etiology and high heterogeneity. To bypass this therapeutic letdown, we previously exploited network medicine and drug repurposing strategies. Leveraging the SAveRUNNER algorithm, we identified several potentially repurposable candidates, including clomipramine (Anafranil®), mianserin (Lantanon®/Tolvon®), and modafinil (Provigil®). Here, we evaluated the in vivo efficacy of these compounds in Drosophila models of ALS, precisely those expressing pan-neuronal human SOD1A4V or SOD1G85R mutations. Our results demonstrate that clomipramine is the most promising candidate, ameliorating lifespan reduction, improving climbing abilities, and mitigating both genomic instability and inflammation, key pathological hallmarks of these SOD1-ALS models. Despite needing further validation in higher organisms, our Drosophila findings represent preliminary yet significant support for clomipramine's action as an add-on treatment for SOD1-ALS.

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