Pharmacological therapeutics in Friedreich ataxia: the present state

Strawser, Cassandra; Schadt, Kimberly; Hauser, Lauren; McCormick, Ashley; Wells, McKenzie; Larkindale, Jane; Lin, Hong; Lynch, David R.

doi:10.1080/14737175.2017.1356721

Cited by 71 publications

(57 citation statements)

References 111 publications

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“…However, this is the only study, so far, which shows elevated expression levels of BDNF in a FRDA model. Two main areas of studies dominate translational research efforts of FRDA: discovery and evaluation of new approaches aimed at alleviating FXN deficiency and discovery of disease biomarkers allowing for objective evaluation of disease progression, prognosis, or treatment efficacy [59][60][61]. miRNAs as small, abundant, and relatively stable molecules, have been evaluated as biomarkers in numerous neurodegenerative disorders, including FRDA [62,63].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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Friedreich's ataxia (FRDA) is a genetic neurodegenerative disease that is caused by guanine-adenine-adenine (GAA) nucleotide repeat expansions in the first intron of the frataxin (FXN) gene. Although present in the intron, this mutation leads to a substantial decrease in protein expression. Currently, no effective treatment is available for FRDA, and, in addition to FXN, other targets with therapeutic potential are continuously sought. As miRNAs can regulate the expression of a broad spectrum of genes, are used as biomarkers, and can serve as therapeutic tools, we decided to identify and characterize differentially expressed miRNAs and their targets in FRDA cells compared to unaffected control (CTRL) cells. In this study, we performed an integrated miRNAseq and RNAseq analysis using the same cohort of primary FRDA and CTRL cells. 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. We 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. We 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. Our 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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…Friedreich Ataxia (FRDA) is an autosomal recessive disorder associated with progressive ataxia, cardiomyopathy, scoliosis, diabetes, and loss of visual and sensorineural hearing function . Degeneration of the dorsal root ganglion (DRG) neurons, the dorsal columns, the dentate nucleus of the cerebellum, and the dorsal spinocerebellar pathways gives rise to ataxia .…”

Section: Introductionmentioning

confidence: 99%

“…At present, no therapy is approved for FRDA . Exogenous IFN‐ γ 1b (ACTIMMUNE), a protein produced by the immune system in response to infections, increases both frataxin messenger RNA (mRNA) and protein levels in a variety of cell types, including cells from FRDA patients .…”

Section: Introductionmentioning

confidence: 99%

Randomized, double‐blind, placebo‐controlled study of interferon‐γ 1b in Friedreich Ataxia

Lynch

Hauser

McCormick

et al. 2019

Ann Clin Transl Neurol

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Objective In vitro, in vivo, and open‐label studies suggest that interferon gamma (IFN‐γ 1b) may improve clinical features in Friedreich Ataxia through an increase in frataxin levels. The present study evaluates the efficacy and safety of IFN‐γ 1b in the treatment of Friedreich Ataxia through a double‐blind, multicenter, placebo‐controlled trial. Methods Ninety‐two subjects with FRDA between 10 and 25 years of age were enrolled. Subjects received either IFN‐γ 1b or placebo for 6 months. The primary outcome measure was the modified Friedreich Ataxia Rating Scale (mFARS). Results No difference was noted between the groups after 6 months of treatment in the mFARS or secondary outcome measures. No change was noted in buccal cell or whole blood frataxin levels. However, during an open‐label extension period, subjects had a more stable course than expected based on natural history data. Conclusions This study provides no direct evidence for a beneficial effect of IFN‐γ1b in FRDA. The modest stabilization compared to natural history data leaves open the possibility that longer studies may demonstrate benefit.

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“…Current strategies for the treatment of FRDA mainly focused on correcting frataxin expression, which intervenes the pathogenetic cascade downstream of frataxin deficiency, enhance antioxidant expression, and even some further gene or protein replacement or cellular therapies 6,33 . In fact, no therapies have been proven to cure or slow disease progression effectively 34 .…”

Section: Discussionmentioning

confidence: 99%

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

Zhao

Lewellen

Wilson

et al. 2020

Sci Rep

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the common clinical symptoms of Friedreich's ataxia (FRDA) include ataxia, muscle weakness, type 2 diabetes and heart failure, which are caused by impaired mitochondrial function due to the loss of frataxin (FXN) expression. Endurance exercise is the most powerful intervention for promoting mitochondrial function; however, its impact on FRDA has not been studied. Here we 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. We 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.Friedreich's ataxia (FRDA) is the most common autosomal recessive ataxia in the Caucasian population 1-4 with detrimental clinical symptoms, including ataxia, muscle weakness, type 2 diabetes and heart failure 5,6 . These symptoms usually first appear in childhood or adolescence and worsen over time. A hypertrophic cardiomyopathy is an important clinical trait, which contributes significantly to disability and early death 7,8 . A high percentage of FRDA patients have glucose intolerance or diabetes mellitus 4 , and exercise capacity is usually severely diminished 9 , leading to wheelchair binding within 10 to 20 years after the disease onset 10 .FRDA is caused by GAA repeat expansions in both alleles of the frataxin (FXN) gene within intron 1 located in chromosome 9 11,12 from normally around 5-30 to >90 6,12 . The GAA expansion mutations lead to reduced expression of frataxin, a mitochondrial protein, which is involved in assembly of iron-sulfur clusters (ISC) and/or function as an iron chaperone or an iron storage protein 13 . Although the precise function of frataxin is not entirely clear yet, substantial evidence shows that frataxin deficiency leads to inefficient use of iron during ISC synthesis, inhibition of ISC formation and/or increased production of reactive oxygen species (ROS) via the Fenton reaction, resulting in iron deposition, mitochondrial dysfunction and oxidative damage 14,15 . It is these abnormal functions in the metabolically active tissues/organs that eventually lead to the onset of clinical symptoms. Unfortunately, no pharmacologic treatment up to date has been proven to impede FRDA progression ...

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Pharmacological therapeutics in Friedreich ataxia: the present state

Cited by 71 publications

References 111 publications

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

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

Randomized, double‐blind, placebo‐controlled study of interferon‐γ 1b in Friedreich Ataxia

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

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