Date Published: January 14, 2019
Publisher: Public Library of Science
Author(s): Amaya Rando, Miriam de la Torre, Anna Martinez-Muriana, Pilar Zaragoza, Antonio Musaro, Sara Hernández, Xavier Navarro, Janne M. Toivonen, Rosario Osta, Hoon Ryu.
Amyotrophic lateral sclerosis (ALS) is a lethal motor neuron disease with no cure. Currently there are only two ALS drugs approved by the FDA, both with a limited therapeutic effect. In the search for drug candidates for ALS, we studied the effect of known stem cell mobilizing agents (treatment) and antimetabolite 5-fluorouracil (5-FU) (anti-treatment) in SOD1G93A model of ALS. Surprisingly, we found that anti-cancer drug 5-FU increases lifespan, delays the disease onset and improves motor performance in ALS mice. Although we were not able to demonstrate the mechanistic basis of the beneficial 5-FU action in ALS mice, our findings suggest that 5-FU or similar drugs are possible drug candidates for the treatment of motor neuron diseases through drug repurposing.
Amyotrophic lateral sclerosis (ALS) is a devastating disease characterized by upper and lower motor neuron (MN) degeneration, progressive muscle paralysis and atrophy . ALS patients typically die from cardiorespiratory failure within 2–5 years after the diagnosis. The only FDA accepted treatments for ALS, riluzole and edaravone, appear to provide only limited benefit to the patients. Thus, new treatments are desperately needed for fighting ALS . While new drugs, cell-based therapies and gene targeting are being investigated for clinical use, the progress is slow because of bottlenecks in the therapeutic development process. Drug repurposing (using an agent already commercialized to treat one disease for the treatment of other diseases) is one of the strategies to reduce the time required to get new treatments on the market. Because repurposing is built on previous R&D efforts, their review by the regulatory agencies is accelerated and new candidate therapies may reach clinical trials and integrate into the clinic more quickly. Several well-known drugs commercialized for other diseases are being investigated in the search for ALS treatment and some of them have already reached clinical trials .
The results of the present study indicate that treatment with a low dose of 5-FU increases the lifespan, delays the disease onset and slightly improves the motor performance of the SOD1G93A mice. Although we were not able to demonstrate the cellular targets behind the beneficial effect of 5-FU, we shall next discuss the potential importance of the findings suggest further studies in order to address the mechanistic basis of the drug effect in the ALS model.