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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.



Functional and Structural Brain Damage in Friedreich's Ataxia

Friedreich's ataxia (FRDA) is a rare hereditary neurodegenerative disorder caused by a GAA repeat expansion in the FXN gene. There is still no cure or quantitative biomarkers reliaby correlating with the progression rate and disease severity. Investigation of functional and structural alterations characterizing white (WM) and gray matter (GM) in FRDA are needed prerequisite to monitor progression and response to treatment. Here the authors report the results of a multimodal cross-sectional MRI study of FRDA including Voxel-Based Morphometry (VBM), diffusion-tensor imaging (DTI), functional MRI (fMRI), and a correlation analysis with clinical severity scores. Twenty-one early-onset FRDA patients and 18 age-matched healthy controls (HCs) were imaged at 3T. All patients underwent a complete cognitive and clinical assessment with ataxia scales. VBM analysis showed GM volume reduction in FRDA compared to HCs bilaterally in lobules V, VI, VIII (L>R), as well as in the crus of cerebellum, posterior lobe of the vermis, in the flocculi and in the left tonsil. Voxel-wise DTI analysis showed a diffuse fractional anisotropy reduction and mean, radial, axial (AD) diffusivity increase in both infratentorial and supratentorial WM. ROI-based analysis confirmed the results showing differences of the same DTI metrics in cortico-spinal-tracts, forceps major, corpus callosum, posterior thalamic radiations, cerebellar penduncles. Additionally, we observed increased AD in superior (SCP) and middle cerebellar peduncles. The WM findings correlated with age at onset (AAO), short-allelle GAA, and disease severity. The intragroup analysis of fMRI data from right-handed 14 FRDA and 15 HCs showed similar findings in both groups, including activation in M1, insula and superior cerebellar hemisphere (lobules V-VIII). Significant differences emerged only during the non-dominant hand movement, with HCs showing a stronger activation in the left superior cerebellar hemisphere compared to FRDA. Significant correlations were found between AAO and the fMRI activation in cerebellar anterior and posterior lobes, insula and temporal lobe. This multimodal neuroimaging protocol suggests that MRI is a useful tool to document the extension of the neurological impairment in FRDA.

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Chemical synthesis of lipophilic methylene blue analogues which increase mitochondrial biogenesis and frataxin levels

As part of an ongoing program to develop potential therapeutic agents for the treatment of the neurodegenerative disease Friedreich׳s ataxia (FRDA), this group has prepared a number of lipophilic methylene blue analogues. Some of these compounds significantly increase mitochondrial biogenesis and frataxin levels in cultured Friedreich's ataxia cells . This data article describes the chemical synthesis and full physicochemical characterization of the new analogues.

Read the entire article HERE

Sudomotor dysfunction is frequent and correlates with disability in Friedreich ataxia

This study set out to evaluate autonomic symptoms and function in Friedreich's Ataxia (FRDA).Twenty-eight FRDA patients and 24 controls underwent clinical/electrophysiological testing. They used the Friedreich's Ataxia Rating Scale (FARS) and the Scales for Outcomes in Parkinson's Disease: Autonomic Questionnaire-SCOPA-AUT to estimate the intensity of ataxia and autonomic complaints, respectively. Cardiovagal tests and the quantitative sudomotor axonal reflex, Q-SART, were then assessed in both groups. In the patient group, there were 11 men with mean age of 31.5 ± 11.1 years. Mean SCOPA-AUT score was 15.1 ± 8.1. Minimum RR interval at rest was shorter in the FRDA group (Median 831.3 × 724.0 ms, p < 0.001). The 30:15 ratio, Valsalva index, E:I ratio, low and high frequency power presented no differences between patients and controls (p > 0.05). Sweat responses were significantly reduced in patients for all sites tested (forearm 0.389 × 1.309 µL; proximal leg 0.406 × 1.107 µL; distal leg 0.491 × 1.232 µL; foot 0.265 × 0.708 µL; p value < 0.05). Sweat volumes correlated with FARS scores. Overall, they found abnormal sudomotor but normal heart rate variability in FRDA. Small cholinergic post-ganglionic fibers were affected in the disease. They conclude that quantification of sudomotor function might be a biomarker for FRDA.

Read the entire article HERE

Increased Frataxin Expression Induced in Friedreich Ataxia Cells by Platinum TALE-VP64s or Platinum TALE-SunTag

Frataxin gene (FXN) expression is reduced in Friedreich's ataxia patients due to an increase in the number of GAA trinucleotides in intron 1. The frataxin protein, encoded by that gene, plays an important role in mitochondria's iron metabolism. This group used a gene editing technology, platinum TALE (plTALE) proteins that target the regulatory region of the FXN gene, fused with a transcriptional activator (TA). These were used to increase the expression of frataxin. They looked at a series of possible combinations of molecules. This permitted selection of 3 constructs that increased FXN gene expression by up to 19-fold in different Friedreich ataxia (FRDA) primary fibroblasts. Adeno-associated viruses were used to deliver the best effectors to the YG8R mouse model to validate their efficiencies in vivo. Our results showed that these selected constructs induced transcriptional activity of the endogenous FXN gene as well as expression of the frataxin protein in YG8R mouse heart by 10-fold and in skeletal muscles by up to 35-fold. The aconitase activity was positively modulated by the frataxin level in mitochondria, and it was, thus, increased in vitro and in vivo by the increased frataxin expression.

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Test-retest reliability of an instrumented electronic walkway system (GAITRite) for the measurement of spatio-temporal gait parameters in young patients with Friedreich's ataxia

Friedreich ataxia (FRDA) affects the spatio-temporal parameters (STP) of gait. The aims of this study were: (1) to measure the reproducibility of STP and gait scores in young patients with FRDA and (2) to describe the characteristics of gait parameters in this population.Thirty-six patients (18 males, 18 females) with diagnosis of FRDA (mean age 16.4 ± 4.5 years) were asked to walk barefoot at a self-selected pace along the pressure sensitive walkway (GAITRite®). Three trials were recorded for each patient and repeated 48 h later. Collected data was put into statistical analysis tests to determine reliability and variability of STPs and two other gait scores: The Functional Ambulation Performance score (FAP) and the Gait Variability Index (GVI). All STPs showed strong or very strong reliability (ICC > 0.7) and a low variability. The two parameters showing the lowest reliability (0.71 and 0.74) were the base of support and the foot progression angle. The FAP score and the GVI showed strong reliability (ICC > 0.8). The authors conclude that the GAITRite system allows feasible and reliable measurements of gait parameters in young patients with FRDA. Lower reliability found for the weakest parameters was attributed to the software automatic errors and the ankle laxity noted in every patient.

Read the entire article HERE

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