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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.


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

A Comprehensive Transcriptome Analysis Identifies FXN and BDNF as Novel Targets of miRNAs in Friedreich's Ataxia Patients

As miRNAs can regulate the expression of a broad spectrum of genes, are used as biomarkers, and can serve as therapeutic tools, the authors decided to identify and characterize differentially expressed miRNAs and their targets in Friedreich's Ataxia (FRDA) cells compared to unaffected control (CTRL) cells. In this study, an integrated miRNAseq and RNAseq analysis using the same cohort of primary FRDA and CTRL cells was performed. The results of the transcriptome studies were supported by bioinformatic analyses and validated by qRT-PCR. miRNA interactions with target genes were assessed by luciferase assays, qRT-PCR, and immunoblotting. In silico analysis identified the FXN transcript as a target of five miRNAs upregulated in FRDA cells. Further studies confirmed that miRNA-224-5p indeed targets FXN, resulting in decreases in mRNA and protein levels. The authors also validated the ability of miRNA-10a-5p to bind and regulate the levels of brain-derived neurotrophic factor (BDNF), an important modulator of neuronal growth. The authors observed a significant decrease in the levels of miRNA-10a-5p and increase in the levels of BDNF upon correction of FRDA cells via zinc-finger nuclease (ZFN)-mediated excision of expanded GAA repeats. This comprehensive transcriptome analyses identified miRNA-224-5p and miRNA-10a-5p as negative regulators of the FXN and BDNF expression, respectively. These results emphasize not only the importance of miRNAs in the pathogenesis of FRDA but also their potential as therapeutic targets for this disease.

Read the entire article HERE

An Overview of the Current State and the Future of Ataxia Treatments

Cerebellar ataxia can be caused by a variety of disorders, including degenerative processes, autoimmune and paraneoplastic illness as well as by gene mutations inherited in autosomal dominant, autosomal recessive, or X-linked fashions. In this review, the authors highlight the treatments for cerebellar ataxia in a systematic way, to provide guidance for clinicians who treat patients with cerebellar ataxia. In addition, therapies currently under development for ataxia are reviewed.

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

Calpain-Inhibitors Protect Frataxin-Deficient Dorsal Root Ganglia Neurons from Loss of Mitochondrial Na+/Ca2+ Exchanger, NCLX, and Apoptosis

Calpains are calcium-dependent proteases activated in apoptotic cell death and neurodegeneration. Dorsal root ganglion (DRG) sensory neurons are among the cellular types most affected in Friedreich Ataxia. The authors have previously demonstrated that frataxin-deficient DRGs show calpain activation, alteration in calcium levels and decreased content of the Na+/Ca2+ exchanger (NCLX). This transporter is involved in mitochondrial calcium efflux. In this study, a time-course analysis of several parameters altered in a frataxin-deficient DRGs is performed. These include decline of NCLX levels, calcium accumulation, mitochondrial depolarization, α-fodrin fragmentation and apoptotic cell death. Furthermore, the effect of the calpain inhibitors MDL28170 and Calpeptin on these parameters were analysed. These inhibitors increase NCLX levels, protect sensory neurons from neurite degeneration and calcium accumulation, and restore mitochondrial membrane potential. In addition, calpain 1 reduction alleviated neurodegeneration in frataxin-deficient DRG neurons. These results strengthen the hypothesis of a central role for calcium homeostasis and calpains in frataxin-deficient dorsal root ganglia neurons.

Read the entire article HERE

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