Development of Novel Mitochondria-Targeted Antioxidants for Improving SOD1-Familial Amyotrophic Lateral Sclerosis Phenotype

Overview

Project Summary

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease and Charcot disease causes muscle weakness and atrophy throughout the body due to the degeneration of upper and lower motor neurons. To date, there is no effective therapy for ALS. Mitochondrial alterations are now considered a central feature that contributes to neurodegeneration in ALS. Indeed, a wealth of evidence indicates that mitochondrial dysfunction, often leading to neuronal death, is observed early in patients, as well as in several ALS models, thus pointing to mitochondria as a valuable disease target. It has been shown that the modulation of mitochondrial biogenesis, the removal of damaged mitochondria through mitophagy, and/or the scavenging of free radicals have clear beneficial effects in ALS models. Yet, none of them was effective when translated to ALS patients so far. In this new project the neuroprotective potential of novel mitochondria-targeted molecules based on dietary antioxidants, which have been recently developed by the Chemistry Medicinal team of Porto (patent publication in progress) will be evaluated on well-established in vitro and in vivo ALS models to explore their therapeutic feasibility by a mitochondria rescue strategy. More specifically, this innovative project has two aims: i) screening of novel mitochondrial-directed molecules for their ability to improve the phenotype of cells of ALS models with and without mutSOD1 and ii) validation of in vivo efficacy of the best candidate in animal model of ALS. To our knowledge, such a study has never been performed before and will be made possible through the collaboration of two teams with specific and complementary expertise, the Medicinal Chemistry team of UP specialized on the design of bioactive compounds and the Mitochondrial Toxicology Experimental therapeutics group of CNC focused on mitochondrial metabolism and the role of that organelle on disease and drug-induced toxicity. Although this is a pre-clinical study, we believe that results from this project may allow to validate a proof-of concept and in turn impact as a new therapeutic approach for the treatment of ALS. Since there is no effective drug to treat or efficiently prolong the life of ALS patients, we believed that the development of this project is a potential to generate value through intellectual property placed on the more effective molecules, contributing to significantly extend the survival and improve the quality of life of patients, reducing also the overall economic burden of this neurological disorder. Complementary, it is expected that this project contributes also to increase the formation of specialized human resources, being the data dissemination of this work will be performed through international peer-reviewed scientific journals and communications in national and international scientific meetings. Science communication activities are also expected.

Main Goals

This innovative project has two aims:
i) screening of novel mitochondrial-directed molecules for their ability to improve the phenotype of cells of ALS models with and without mutSOD1 and
ii) validation of in vivo efficacy of the best candidate in animal model of ALS.

Project Details