Drug Discovery/Improving Clinical Outcomes:

Title: Endurance and resistance exercise mitigate Friedreich’s ataxia
PI: Zhen Yan, University of Virginia
*Funded in part by the Phillip Bennett Memorial Fund

This research grant builds on prior funded work evaluating the impact of exercise in an FA mouse model.  The overall objectives of this proposal are to determine if resistance exercise and endurance exercise are equally effective in preventing symptoms of FRDA in mice and to elucidate how endurance exercises exert the positive impact. The proposed studies will provide new insights into interventions to the etiology of FRDA and pave the way for the development of innovative exercise-based interventions for management and therapy. 


Title: Measurement of the TCA cycle rate in the dentate nucleus in Friedreich’s Ataxia
PI: Pierre-Gilles Henry and Christophe Lenglet, University of Minnesota
*Funded in Partnership with the Cure FA Foundation

This is a novel biomarker study. In vivo carbon-13 magnetic resonance spectroscopy (13C MRS) allows non-invasive measurement of metabolic rates in living tissues following systemic administration of a 13C labeled substrate. In particular, the glucose metabolism can be measured non-invasively in the human brain. In this project, similar measurements of glucose metabolism will be evaluated in the cerebellum. These would be the first metabolic measurements in the human cerebellum using 13C MRS, and the first such measurements in individuals with FA.

Cell and Animal Models:

Title: Development of a novel iPSC-derived neuronal cell model for Friedreich’s ataxia: generation of stable doxycycline-inducible expression of progerin in FRDA neuronal cells
PI: Joel Gottesfeld (Baohu Ji, Research Fellow), The Scripps Research Institute
*Funded in Partnership with FARA Ireland.

This research grant supports the development of a novel cellular model for Friedreich’s ataxia (FRDA) where potential therapeutic approaches can be tested. They will generate stable doxycycline-dependent inducible expression of progerin in FRDA iPSC-derived neuronal cells. Progerin is a truncated form of the nuclear protein Lamin A and is responsible for the early onset aging disease, Progeria Syndrome. Based on previous studies in the literature, forced expression of progerin in neuronal cells has been demonstrated to successfully model late-onset diseases, taking into account age progression properties.  Expression of progerin in FRDA neurons should reproducible phenotypes of FRDA, such as mitochondrial dysfunction and oxidative stress.

Mechanisms/Pathophysiology of the Disease:

Title: Structural dynamics and the consolidation of protein function in protein complexes involved in the biosynthesis of iron-sulfur clusters: Quaternary addition of small Trojan tutor proteins
PI: Javier Santos, Universidad de Buenos Aires, Argentina

Frataxin and several other proteins are essential in forming iron-sulfur (Fe-S) clusters. Individuals with FA are deficient in frataxin and thus deficient in Fe-S clusters. This research will evaluate the structural dynamics of these proteins in the Fe-S cluster complex and evaluate variants of proteins as therapeutic strategies to restore Fe-S clusters.

Title: The pathogenesis of Friedreich ataxia
PI: Arnulf H. Koeppen, MD, Albany Research Institute

Dr. Koeppen is the careful steward and curator of the largest FA tissue repository. When individuals with FA pass away they can donate tissues for research, and they go to Dr. Koeppen for careful analysis. Dr. Koeppen will extend his research of these tissues into proteomic analysis. The goal of this research is to identify those proteins-of-interest in FA that are up-regulated or down-regulated relative to levels in non-FA subjects, and to determine the functional consequences of these differences.

Title: Studying the role of brown fat in Friedreich’s ataxia
PI: Katia Aquilano, University of Rome Tor Vergata, Italy

FRDA patients frequently develop diabetes mellitus, and accumulation of intracellular triglycerides is found in many cells and tissues, thus implying defective brown fat activity and utilization of lipids. This research will evaluate and characterize the abnormalities of brown fat in the FA mouse model and then evaluate different dietary or supplements to improve function.