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Scientific News

FARA funds research progress

In this section, you will find the most recent FA research publications, many of which are funded by FARA, as well as information on upcoming conferences and symposiums. You can search for articles by date using the archive box in the right hand column. To locate FARA Funded or Supported Research, click the hyperlink in the right hand column. You may also search for specific content using key words or phrases in the search button at the top right of your screen. Please be sure to visit other key research sections of our website for information on FARA’s Grant Program and the Treatment Pipeline.

Psychometric properties of the Friedreich Ataxia Rating Scale

This study aims at investigating the psychometric properties of the Friedreich Ataxia Rating Scale neurologic examination (FARSn) and its subscores, as well as the influence of the modifications resulting in the now widely used modified FARS (mFARS) examination. Based on cross-sectional FARS data from the FA-Clinical Outcome Measures cohort, this group conducted correlation-based psychometric analyses to investigate the interplay of items and subscores within the FARSn/mFARS constructs. The results provide support for both the FARSn and the mFARS constructs, as well as individually for their upper limb and lower limb coordination components. The omission of the peripheral nervous system subscore (D) and 2 items of the bulbar subscore (A) in the mFARS strengthens the overall construct compared with the complete FARS. A correlation-based psychometric analysis of the neurologic FARSn score justifies the overall validity of the scale. In addition, omission of items of limited functional significance as created in the mFARS improves the features of the measures. Such information is crucial to the ongoing application of the mFARS in natural history studies and clinical trials. Additional analyses of longitudinal changes will be necessary to fully ascertain its utility, especially in nonambulant patients.

Read the entire article HERE

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. In this review, the authors first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. They then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability. Next, they describe the consequences of the presence of long structure-forming repeats at the molecular level: somatic and intergenerational instability, fragility, and repeat-induced mutagenesis. The reasons for gender bias in intergenerational repeat instability and the tissue specificity of somatic repeat instability is then discussed. The authors also review the known pathways in which DNA replication, transcription, DNA repair, and chromatin state interact and thereby promote repeat instability. They then discuss possible reasons for the persistence of disease-causing DNA repeats in the genome. They describe evidence suggesting that these repeats are a payoff for the advantages of having abundant simple-sequence repeats for eukaryotic genome function and evolvability. Finally, the authors discuss two unresolved fundamental questions: (i) why does repeat behavior differ between model systems and human pedigrees, and (ii) can the current knowledge on repeat instability mechanisms be used to cure repeat expansion diseases?

Read the entire article HERE

The Potential of the Novel NAD+ Supplementing Agent, SNH6, as a Therapeutic Strategy for the Treatment of Friedreich's Ataxia

In this study, the activity of the novel compound, 6-methoxy-2-salicylaldehyde nicotinoyl hydrazone (SNH6), was assessed in vivo using the well-characterized muscle creatine kinase (MCK) conditional frataxin knockout (KO) mouse model of Friedreich's ataxia (FA). The design of SNH6 incorporated a dual-mechanism mediating: (1) NAD+-supplementation to restore cardiac bioenergetics; and (2) iron chelation to remove toxic mitochondrial iron. In these studies, MCK wild-type (WT) and KO mice were treated for 4-weeks from the asymptomatic age of 4.5-weeks to 8.5-weeks of age, where the mouse displays an overt cardiomyopathy. SNH6-treatment significantly elevated NAD+ and markedly increased NAD+ consumption in WT and KO hearts. In SNH6-treated KO mice, nuclear Sirt1 activity was also significantly increased together with the NAD+-metabolic product, nicotinamide (NAM). Therefore, NAD+-supplementation by SNH6 aided mitochondrial function and cardiac bioenergetics. SNH6 also chelated iron in cultured cardiac cells and also removed iron-loading in vivo from the MCK KO heart. Despite its dual beneficial properties of supplementing NAD+ and chelating iron, SNH6 did not mitigate cardiomyopathy development in the MCK KO mouse. Collectively, SNH6 is an innovative therapeutic with marked pharmacological efficacy, which successfully enhanced cardiac NAD+ and nuclear Sirt1 activity and reduced cardiac iron-loading in MCK KO mice. No other pharmaceutical yet designed exhibits both these effective pharmacological properties.

Read the entire article HERE

Ocular Involvement in Friedreich Ataxia Patients and its Relationship with Neurological Disability, a Follow-up Study

This study compared functional and structural visual changes in Friedreich ataxia (FRDA) patients with healthy controls (HC) and correlated these changes with neurological disability. Eight FRDA Spanish patients and eight HC were selected from 2014 to 2018. Best corrected visual acuity (BCVA), visual field (VF), optic coherence tomography (OCT), and neurological disability measured by "scale for the assessment and rating of ataxia" (SARA) were taken in a basal exploration and repeated after 6 months. A linear mixed analysis and Bonferroni p-value correction were performed. FRDA baseline and follow-up patients showed statistically significant decreases in BCVA, VF, and OCT parameters compared with the HC. Some of the VF measurements and most of the OCT parameters had an inverse mild-to-strong correlation with SARA. Moreover, the analysis of the ROC curve demonstrated that the peripapillary retinal nerve fiber layer (pRNFL) average thickness was the best parameter to discriminate between FRDA patients and HC. The follow-up study showed a progression in OCT parameters. Findings showed a sequential effect in pRNFL, ganglion cell complex (GCC), and macula. The VF and the OCT could be useful biomarkers in FRDA, both for their correlation with neurological disease as well as for their ability to evaluate disease progression.

Read the entire article HERE

The NRF2 Signaling Network Defines Clinical Biomarkers and Therapeutic Opportunity in Friedreich's Ataxia

Mounting evidence suggests that impairment in iron-sulfur cluster biosynthesis and iron accumulation in the mitochondria increase oxidative stress susceptibility and reactive oxygen species production in Friedreich's ataxia (FA). The FA pathologic picture is worsened by a defective regulation of the expression and signaling pathway modulation of the transcription factor NF-E2 p45-related factor 2 (NRF2), one of the fundamental mediators of the cellular antioxidant response. NRF2 protein downregulation and impairment of its nuclear translocation can compromise the adequate cellular response to the frataxin depletion-dependent redox imbalance. As NRF2 stability, expression, and activation can be modulated by diverse natural and synthetic compounds, efforts have been made in recent years to understand if regulating NRF2 signaling might ameliorate the pathologic defects in FA. Here the authors provide an analysis of the pharmaceutical interventions aimed at restoring the NRF2 signaling network in FA, elucidating specific biomarkers useful for monitoring therapeutic effectiveness, and developing new therapeutic tools.

Read the entire article HERE

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