A Drug Combination Rescues Frataxin-Dependent Neural and Cardiac Pathophysiology in FA Models

Rosella Abeti; Mittal Jasoliya; Sahar Al-Mahdawi; Mark Pook; Cristina Gonzalez-Robles; Chun Kiu Hui; Gino Cortopassi; Paola Giunti

doi:10.3389/fmolb.2022.830650

A Drug Combination Rescues Frataxin-Dependent Neural and Cardiac Pathophysiology in FA Models

Front Mol Biosci. 2022 May 19:9:830650. doi: 10.3389/fmolb.2022.830650. eCollection 2022.

Authors

Rosella Abeti¹, Mittal Jasoliya², Sahar Al-Mahdawi³, Mark Pook³, Cristina Gonzalez-Robles¹, Chun Kiu Hui², Gino Cortopassi², Paola Giunti¹

Affiliations

¹ Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL, Institute of Neurology, London, United Kingdom.
² Department of Molecular Biosciences, School of Veterinary Medicine, UC Davis, Davis, CA, United States.
³ Department of Life Sciences, Institute of Environment, Health, and Societies, College of Health and Life Sciences, Division of Biosciences, Brunel University London, Uxbridge, United Kingdom.

Abstract

Friedreich's ataxia (FA) is an inherited multisystemic neuro- and cardio-degenerative disorder. Seventy-four clinical trials are listed for FA (including past and present), but none are considered FDA/EMA-approved therapy. To date, FA therapeutic strategies have focused along two main lines using a single-drug approach: a) increasing frataxin and b) enhancing downstream pathways, including antioxidant levels and mitochondrial function. Our novel strategy employed a combinatorial approach to screen approved compounds to determine if a combination of molecules provided an additive or synergistic benefit to FA cells and/or animal models. Eight single drug molecules were administered to FA fibroblast patient cells: nicotinamide riboside, hemin, betamethasone, resveratrol, epicatechin, histone deacetylase inhibitor 109, methylene blue, and dimethyl fumarate. We measured their individual ability to induce FXN transcription and mitochondrial biogenesis in patient cells. Single-drug testing highlighted that dimethyl fumarate and resveratrol increased these two parameters. In addition, the simultaneous administration of these two drugs was the most effective in terms of FXN mRNA and mitobiogenesis increase. Interestingly, this combination also improved mitochondrial functions and reduced reactive oxygen species in neurons and cardiomyocytes. Behavioral tests in an FA mouse model treated with dimethyl fumarate and resveratrol demonstrated improved rotarod performance. Our data suggest that dimethyl fumarate is effective as a single agent, and the addition of resveratrol provides further benefit in some assays without showing toxicity. Therefore, they could be a valuable combination to counteract FA pathophysiology. Further studies will help fully understand the potential of a combined therapeutic strategy in FA pathophysiology.

Keywords: Dimethyl fumarate (DMF); Frataxin (FXN); Friedreich’s Ataxia (FA); Mitochondrial membrane potential (ΔΨm); Reactive Oxygen species (ROS); Resveratrol (Resv).