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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.

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

Analysis of Putative Epigenetic Regulatory Elements in the FXN Genomic Locus

The molecular mechanisms associated with Friedreich´s ataxia (FRDA) are still poorly understood and most studies on FXN gene regulation have been focused on the region around the minimal promoter and the region in which triplet expansion occurs. Nevertheless, since there could be more epigenetic changes involved in the reduced levels of FXN transcripts, the aim of this study was to obtain a more detailed view of the possible regulatory elements by analyzing data from ENCODE and Roadmap consortia databases. This bioinformatic analysis indicated new putative regulatory regions within the FXN genomic locus, including exons, introns, and upstream and downstream regions. Moreover, the region next to the end of intron 4 is of special interest, since the enhancer signals in FRDA-affected tissues are weak or absent in this region, whilst they are strong in the rest of the analyzed tissues. Therefore, these results suggest that there could be a direct relationship between the absence of enhancer sequences in this specific region and their predisposition to be affected in this pathology.

Read the entire article HERE

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

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