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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.



Structural signature of classical versus late-onset friedreich's ataxia by Multimodality brain MRI

Friedreich's ataxia (FRDA) is the most common autosomal-recessive ataxia worldwide. It is characterized by early onset, sensory abnormalities, and slowly progressive ataxia. However, some individuals manifest the disease after the age of 25 years and are classified as late-onset FRDA (LOFA). Therefore, we propose a MRI-based study to investigate which anatomical substrates are involved in classical (cFRDA) and LOFA.

The group enrolled 36 patients (13 with LOFA) and 29 healthy controls. All subjects underwent magnetic resonance imaging to assess gray and white matter in specific structures. They found that both groups presented gray matter atrophy mostly in the motor cortex. They found white matter abnormalities in the cerebellar peduncles, pyramidal tracts, midbrain, pons, and medulla oblongata for both groups, but the microstructural abnormalities in the cFRDA group were more widespread. In addition, they found that the corticospinal tract presented more severe microstructural damage in the LOFA group. Finally, the midbrain volume of the cFRDA, but not of the LOFA group, correlated with disease duration and severity.

The cFRDA and LOFA groups have similar, but not identical neuroimaging damage pattern. These structural differences might help to explain the phenotypic variability observed in FRDA.

Read more HERE

Erythropoietin and small molecule agonists of the tissue-protective erythropoietin receptor increase FXN expression in neuronal cells in vitro and in Fxn-deficient KIKO mice in vivo

Friedreich's ataxia (FRDA) is a progressive neurodegenerative disease caused by reduced levels of the mitochondrial protein frataxin (FXN). Recombinant human erythropoietin (rhEPO) increased FXN protein in vitro and in early clinical studies, while no published reports evaluate rhEPO in animal models of FRDA. STS-E412 and STS-E424 are novel small molecule agonists of the tissue-protective EPO receptor, which do not affect the receptor that relates to red blood cell synthesis. Int his study, the group finds that rhEPO, STS-E412 and STS-E424 increase FXN expression in vitro and in vivo. RhEPO, STS-E412 and STS-E424 increase FXN by up to 2-fold in primary human neuronal cells and in retinoic-acid differentiated murine P19 cells. In primary human cortical cells, the increase in FXN protein was accompanied by an increase in FXN mRNA, detectable within 4 h. RhEPO and low nanomolar concentrations of STS-E412 and STS-E424 also increase FXN in normal and FRDA patient-derived PBMC by 20%-40% within 24 h, an effect that was comparable to that by HDAC inhibitor 4b. In vivo, STS-E412 increased Fxn mRNA and protein in wild-type C57BL6/j mice. RhEPO, STS-E412, and STS-E424 increase FXN expression in the heart of FXN-deficient KIKO mice. In contrast, FXN expression in the brains of KIKO mice increased following treatment with STS-E412 and STS-E424, but not following treatment with rhEPO. Unexpectedly, rhEPO-treated KIKO mice developed severe splenomegaly, while no splenomegaly was observed in STS-E412- or STS-E424-treated mice. RhEPO, STS-E412 and STS-E424 upregulate FXN expression in vitro at equal efficacy, however, the effects of the small molecules on FXN expression in the CNS are superior to rhEPO in vivo.

Read more HERE

Dimethyl Fumarate Mediates Nrf2-dependent Mitochondrial Biogenesis in Mice and Humans

The induction of mitochondrial biogenesis could potentially alleviate mitochondrial and muscle disease. We show here that dimethyl fumarate (DMF) dose-dependently induces mitochondrial biogenesis and function dosed to cells in in vitro, and also dosed in vivo to mice and humans. The induction of mitochondrial gene expression is more dependent on its target Nrf2 than hydroxycarboxylic acid receptor 2 (HCAR2). Thus, DMF induces mitochondrial biogenesis primarily through its action on Nrf2, and is the first drug demonstrated to increase mitochondrial biogenesis with in vivo human dosing. The observation that DMF stimulates mitochondrial biogenesis, gene expression and function suggests that it could be considered for mitochondrial disease therapy and/or therapy in muscle disease in which mitochondrial function is important.

Read more HERE

Normalization of timed neuropsychological tests with the PATA rate and nine-hole pegboard tests

Friedrich'a Ataxia patients have neurological impairment that causes physical impairments, but existing timed neuropsychological tests do not take this into account during scoring procedures. This paper proposes a normalization method based on the PATA Rate Task (PRT) and on the nine-hole pegboard test (9HPT) as a measure of dysarthria and upper limb dysfunction.They tested 65 healthy controls on timed neuropsychological tests (Attentional Matrices [AM], Trail Making Test, Symbol Digit Modalities Test, Verbal Fluencies) to determine the time spent on phonation or on hand movement during test execution. They developed correction formulas to normalize test times considering the patient's PRT/9HPT, their normality limits, and the test timing. They tested the method on 24 patients with Friedreich Ataxia (FRDA), as a model of motor and speech impairment.

They found that in healthy controls, phonation or hand movement is 13.5-61.7% of total test time. In FRDA patients, the effect of normalization improved all test results (range: 0.51-48.4%; p

Read more HERE

Dysphagia in Friedreich Ataxia

The objective of the study was to comprehensively characterise dysphagia in Friedreich ataxia (FRDA) and identify predictors of penetration/aspiration during swallowing. We also investigated the psychosocial impact of dysphagia on individuals with FRDA. Sixty participants with FRDA were screened for dysphagia using a swallowing quality of life questionnaire (Swal-QOL) and case history. Individuals reporting dysphagia underwent a standardised oromotor assessment (Frenchay Dysarthria Assessment, 2, FDA-2) and videofluoroscopic study of swallowing (VFSS). Data were correlated with disease parameters (age at symptom onset, age at assessment, disease duration, FXN intron 1 GAA repeat sizes, and Friedreich Ataxia Rating Scale (FARS) score).

Ninety-eight percent (59/60) of participants reported dysphagia, of whom 35 (58.3%) underwent FDA-2 assessment, and 38 (63.3%) underwent VFSS. Laryngeal, respiratory, and tongue dysfunction was observed on the FDA-2. A Penetration-Aspiration Scale score above 3 (deemed significant airway compromise based on non-clinical groups) was observed on at least one consistency in 13/38 (34.2%) participants. All of those who aspirated (10/38, 26.3%) did so silently, with no overt signs of airway entry such as reflexive cough.

Significant correlations were observed between dysphagic symptoms and disease duration and severity. No reliable predictors of penetration or aspiration were identified. Oropharyngeal dysphagia is commonly present in individuals with FRDA and worsens with disease duration and severity. Individuals with FRDA are at risk of aspiration at any stage of the disease and should be reviewed regularly. Instrumental analysis remains the only reliable method to detect aspiration in this population. Dysphagia significantly affects the quality of life of individuals with FRDA.

Read more HERE

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