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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.

Neurofilament Light Chain as a Potential Biomarker of Disease Status in Friedreich Ataxia

The present study evaluates serum neurofilament light chain (NfL) as a biomarker of disease features in Friedreich's ataxia (FRDA). NfL levels from serum of 117 subjects (85 FRDA patients, 13 carriers, and 19 controls) were assayed and correlated with disease features such as smaller GAA repeat length (GAA1), age, sex, and level of neurological dysfunction. Mean serum NfL levels were higher in FRDA patients than in carriers or unaffected controls in two independent cohorts of subjects. In longitudinal samples from FRDA patients drawn monthly or 1 year apart, values changed minimally. No difference was noted between carriers and controls. NfL levels correlated positively with age in controls and carriers of similar age, (Rs = 0.72, p < 0.0005), whereas NfL levels inversely correlated with age in FRDA patients (Rs = - 0.63, p < 0.001). NfL levels were not associated with sex or GAA1 length in patients, and linear regression revealed a significant relationship between NfL levels in the cohort with age (coefficient = - 0.36, p < 0.001), but not sex (p = 0.64) or GAA1 (p = 0.13). Because NfL is elevated in patients, but decreases with age and disease progression, our results suggest that age is the critical determinant of NfL in FRDA (rather than clinical or genetic severity).

Read the entire article HERE

Primary Proprioceptive Neurons From Human Induced Pluripotent Stem Cells: A Cell Model for Afferent Ataxias

Human induced pluripotent stem cells (iPSCs) are used to generate models of human diseases that recapitulate the pathogenic process as it occurs in affected cells. Many differentiated cell types can currently be obtained from iPSCs, but no validated protocol is yet available to specifically generate primary proprioceptive neurons. Proprioceptors are affected in a number of genetic and acquired diseases, including Friedreich ataxia (FRDA). To develop a cell model that can be applied to conditions primarily affecting proprioceptors, a protocol to differentiate iPSCs into primary proprioceptive neurons was established. The authors modified the dual-SMAD inhibition/WNT activation protocol, previously used to generate nociceptor-enriched cultures of primary sensory neurons from iPSCs, to favor instead the generation of proprioceptors. The authors succeeded in substantially enriching iPSC-derived primary sensory neuron cultures for proprioceptors, up to 50% of finally differentiated neurons, largely exceeding the proportion of 7.5% normally represented by these cells in dorsal root ganglia. This study also showed that almost pure populations of proprioceptors can be purified from these cultures by fluorescence-activated cell sorting. Finally, the authors demonstrated that the protocol can be used to generate proprioceptors from iPSCs from FRDA patients, providing a cell model for this genetic sensory neuronopathy.

Read the entire article HERE

Progress Towards Drug Discovery for Friedreich's Ataxia: Identifying Synthetic Oligonucleotides That More Potently Activate Expression of Human Frataxin Protein

The authors have previously demonstrated that synthetic antisense oligonucleotides or duplex RNAs that are complementary to the expanded AAG repeat can activate expression of FXN and return levels of FXN protein to near normal. The potency of these compounds, however, was too low to encourage vigorous pre-clinical development. The authors now report testing of "gapmer" oligonucleotides consisting of a central DNA portion flanked by chemically modified RNA that increases binding affinity. This study finds that gapmer antisense oligonucleotides are several fold more potent activators of FXN expression relative to previously tested compounds. The potency of FXN activation is similar to a potent benchmark gapmer targeting the nuclear noncoding RNA MALAT-1, suggesting that this approach has potential for developing more effective compounds to regulate FXN expression in vivo.

Read the entire article HERE

Long-term voluntary running prevents the onset of symptomatic Friedreich's ataxia in mice

Endurance exercise is the most powerful intervention for promoting mitochondrial function; however, its impact on Friedreich's ataxia (FRDA) has not been studied. Here the authors found that mice with genetic knockout and knock-in of the Fxn gene (KIKO mice) developed exercise intolerance, glucose intolerance and moderate cardiac dysfunction at 6 months of age. These abnormalities were associated with impaired mitochondrial respiratory function concurrent with reduced iron regulatory protein 1 (Irp1) expression as well as increased oxidative stress, which were not due to loss of mitochondrial content and antioxidant enzyme expression. Importantly, long-term (4 months) voluntary running in KIKO mice starting at a young age (2 months) completely prevented the functional abnormalities along with restored Irp1 expression, improved mitochondrial function and reduced oxidative stress in skeletal muscle without restoring Fxn expression. The authors conclude that endurance exercise training prevents symptomatic onset of FRDA in mice associated with improved mitochondrial function and reduced oxidative stress. These preclinical findings may pave the way for clinical studies of the impact of endurance exercise in FRDA patients.

Read the entire article HERE

The Assessment of Upper Limb Functionality in Friedreich Ataxia via Self-Feeding Activity

The objective assessment of motor impairment resulting from neurological disorders forms the basis for effective rehabilitation and therapeutic programs. Such assessments conducted through the engagement of suitable daily activities can serve as an effective surrogate measure for the assessment of independent living. This study considers an instrumented spoon in the assessment of upper-limb functionality through the self-feeding activity of a group of individuals clinically diagnosed with the debilitating condition, Friedreich ataxia (FRDA). Thirty-five subjects with FRDA (34±14 years old) and 14 age-matched healthy subjects performed three cycles of self-feeding consisting of grasping, scooping, transferring food to mouth and returning the spoon. Parameters relating to the feeding rate, trajectory of the rotation, range of motion and movement variability with specific attention to each segment were considered for the capture of ataxia pertaining to the disability. Movement variability measured by Dynamic Time Warping (DTW) resulted in an average accuracy of 96% in the diagnosis of ataxia (separation of the two cohorts). The severity of ataxia estimated using a combination of features from Random Forest (RF) increased the correlation with the clinical estimates of ataxia by 13% and achieved higher coefficient (0.72 in patient scale) than the currently used tests (Box & Block, Pegboard). While the overall results provided an objective, daily activity based means of capturing intrinsic abnormalities, the different segments of the task demonstrated the presence of ataxia in a spatial context concurring with relevant clinical observations.

Read the entire article HERE

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