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FARA Funded Research

Your generous support has funded all the research listed below.

For more information on FARA-funded research & scientists, please visit FARA Supported Research, Active Clinical Trials and the Featured Scientist.

Identification of a Novel Oleic Acid Analog with Protective Effects in Multiple Cellular Models of Friedreich Ataxia

Previous studies suggested that cell death in (Friedreich Ataxia) FRDA may involve ferroptosis, an iron-dependent form of cell death requiring lipid peroxidation. Based on reports that oleic acid acts as a ferroptosis inhibitor, the authors evaluated whether it, other fatty acids, and fatty acid derivatives could rescue viability in cellular models of FRDA. they identified a trifluoromethyl alcohol analog of oleic acid that was significantly more potent than oleic acid itself. Further evaluation indicated that the effects were stereoselective, although a specific molecular target has not yet been identified. This work provides a potential starting point for therapeutics to treat FRDA, as well as a valuable probe molecule to interrogate FRDA pathophysiology.

Read the Entire Article Here

Relationship between activity and stability: Design and characterization of stable variants of human frataxin

Frataxin (FXN) is an essential protein that forms part of a supercomplex dedicated to the iron-sulfur (Fe-S) cluster assembly within the mitochondrial matrix. Recently, the way in which FXN interacts with the rest of the subunits of the supercomplex was uncovered. This opens a window to explore relationships between structural dynamics and function. In this study, the authors prepared a set of FXN variants spanning a broad range of conformational stabilities. Variants S160I, S160 M and A204R were more stable than the wild-type and showed similar biological activity. Additionally, we prepared SILCAR, a variant that combines S160I, L203C and A204R mutations. SILCAR was 2.4 kcal mol-1 more stable and equally active. Some of the variants were significantly more resistant to proteolysis than the wild-type FXN. SILCAR showed the highest resistance, suggesting a more rigid structure. It was corroborated by means of molecular dynamics simulations. Relaxation dispersion NMR experiments comparing SILCAR and wild-type variants suggested similar internal motions in the microsecond to millisecond timescale. Instead, variant S157I showed higher denaturation resistance but a significant lower function, similarly to that observed for the FRDA variant N146K. The authors concluded that the contribution of particular side chains to the conformational stability of FXN might be highly subordinated to their impact on both the protein function and the stability of the functional supercomplex.

Read the entire article HERE

Mitochondrial Damage and Senescence Phenotype of Cells Derived From a Novel Frataxin G127V Point Mutation Mouse Model of Friedreich's Ataxia

A prevalent missense mutation among Friedreich's ataxia (FRDA) patients changes a glycine at position 130 to valine (G130V). Herein, we report generation of the first mouse model harboring a Fxn point mutation. Changing the evolutionarily conserved glycine 127 in mouse Fxn to valine results in a failure to thrive phenotype in homozygous animals and a substantially reduced number of offspring. Like G130V in FRDA, the G127V mutation results in a dramatic decrease of Fxn protein without affecting transcript synthesis or splicing. FxnG127V mouse embryonic fibroblasts exhibit significantly reduced proliferation and increased cell senescence. These defects are evident in early passage cells and are exacerbated at later passages. Furthermore, increased frequency of mitochondrial DNA (mtDNA) lesions and fragmentation are accompanied by marked amplification of mtDNA in FxnG127V cells. Bioenergetics analyses demonstrate higher sensitivity and reduced cellular respiration of FxnG127V cells upon alteration of fatty acid availability. Importantly, substitution of FxnWT with FxnG127V is compatible with life and cellular proliferation defects can be rescued by mitigation of oxidative stress via hypoxia or induction of the NRF2 pathway. We propose FxnG127V cells as a simple and robust model for testing therapeutic approaches for FRDA.

Read the entire article HERE

HMTase Inhibitors as a Potential Epigenetic-Based Therapeutic Approach for Friedreich's Ataxia

Currently there is no effective treatment for Friedreich's ataxia (FRDA) and patients die prematurely. Recent findings suggest that abnormal GAA expansion plays a role in histone modification, subjecting the FXN gene to heterochromatin silencing. Therefore, as an epigenetic-based therapy, we investigated the efficacy and tolerability of two histone methyltransferase (HMTase) inhibitor compounds, BIX0194 (G9a-inhibitor) and GSK126 (EZH2-inhibitor), to specifically target and reduce H3K9me2/3 and H3K27me3 levels, respectively, in FRDA fibroblasts. We show that a combination treatment of BIX0194 and GSK126, significantly increased FXN gene expression levels and reduced the repressive histone marks. However, no increase in frataxin protein levels was observed. Nevertheless, our results are still promising and may encourage to investigate HMTase inhibitors with other synergistic epigenetic-based therapies for further preliminary studies.

Read the entire article HERE

CRISPR-Cas9 Gene Editing of Hematopoietic Stem Cells From Patients With Friedreich's Ataxia

These investigators have previously reported that syngeneic hematopoietic stem and progenitor cell (HSPC) transplantation prevented neurodegeneration in the Friedreich's Ataxia (FRDA) mouse model YG8R. This group showed that the mechanism of rescue was mediated by the transfer of the functional frataxin from HSPC-derived microglia/macrophage cells to neurons/myocytes. In this study, the first step toward an autologous HSPC transplantation using the CRISPR-Cas9 system for FRDA is reported. The authors first identified a pair of CRISPR RNAs (crRNAs) that efficiently removes the GAA expansions in human FRDA lymphoblasts, restoring the non-pathologic level of frataxin expression and normalizing mitochondrial activity. They also optimized the gene-editing approach in HSPCs isolated from healthy and FRDA patients' peripheral blood and demonstrated normal hematopoiesis of gene-edited cells in vitro and in vivo. The procedure did not induce cellular toxic effect or major off-target events, but a p53-mediated cell proliferation delay was observed in the gene-edited cells. This study provides the foundation for the clinical translation of autologous transplantation of gene-corrected HSPCs for FRDA.

Read the entire article HERE

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