Emerging Therapies in Friedreich’s Ataxia

Aranca, Tanya V.; Jones, Tracy; Shaw, Jessica; Staffetti, Joseph; Ashizawa, Tetsuo; Kuo, Sheng‐Han; Fogel, Brent L.; Wilmot, George; Perlman, Susan; Onyike, Chiadi U.; Ying, Sarah H.; Zesiewicz, Theresa A.

doi:10.2217/nmt.15.73

Cited by 58 publications

(43 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Healthy matched subjects were identified by advertisements. Written informed consent was obtained under Age at 1st symptom, yr N/A 11.5 ± 5.0 (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) Age at diagnosis, yr N/A 14.7 ± 6.5 Duration from 1st symptom, yr N/A 13.0 ± 5.2 (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) Duration from diagnosis, yr N/A 10.0 ± 5.4 (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)…”

Section: Study Populationmentioning

confidence: 99%

“…4,5 The recent focus on disease-modifying therapies for FRDA has highlighted the need for validated biomarkers of disease progression. 6,7 The current standards to assess FRDA disease severity are the two clinical scales Friedreich's Ataxia Rating Scale (FARS) 8,9 and Scale for the Assessment and Rating of Ataxia (SARA). 10 Based on a body of literature demonstrating the presence of a distal axonopathy and abnormal quantitative sensory thresholds in FRDA, indicative of unmyelinated nerve fiber pathology, 11 we hypothesized that quantification of View this article online at wileyonlinelibrary.com.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Corneal confocal microscopy: Neurologic disease biomarker in Friedreich ataxia

Pagovich

Zhao

et al. 2018

Annals of Neurology

View full text Add to dashboard Cite

Objective: Friedreich ataxia (FRDA), an autosomal recessive neurodegenerative disease caused by mutations in the gene encoding for the mitochondrial protein frataxin, is characterized by ataxia and gait instability, immobility, and eventual death. We evaluated corneal confocal microscopy (CCM) quantification of corneal nerve morphology as a novel, noninvasive, in vivo quantitative imaging biomarker for the severity of neurological manifestations in FRDA. Methods: Corneal nerve fiber density, branch density, and fiber length were quantified in individuals with FRDA (n = 23) and healthy age-matched controls (n = 14). All individuals underwent genetic testing and a detailed neurological assessment with the Scale for the Assessment and Rating of Ataxia (SARA) and Friedreich's Ataxia Rating Scale (FARS). A subset of individuals with FRDA who were ambulatory underwent quantitative gait assessment. Results: CCM demonstrated a significant reduction in nerve fiber density and length in FRDA compared to healthy controls. Importantly, CCM parameters correlated with genotype, SARA and FARS neurological scales, and linear regression modeling of CCM nerve parameter-generated equations that predict the neurologic severity of FRDA. Interpretation: Together, the data suggest that CCM quantification of corneal nerve morphology is a rapid, sensitive imaging biomarker for quantifying the severity of neurologic disease in individuals with FRDA. ANN NEUROL 2018;84:893-904 F riedreich ataxia (FRDA), an inherited autosomal recessive disorder with an incidence of 1:50,000 in the Caucasian population, is characterized by progressive ataxia, gait instability, immobility, and eventual death. 1,2 FRDA is caused by a guanine-adenine-adenine (GAA) trinucleotide repeat expansion in the first intron of the frataxin (FXN) gene, which causes epigenetic silencing of the FXN gene and decreases levels of FXN mRNA. 2 The resulting deficiency of FXN protein causes an imbalance of iron homeostasis in the mitochondria, with increased oxygen radical production and oxidative stress. 3 FRDA is characterized by spinocerebellar ataxia, dysarthria, pyramidal weakness, sensory loss, optic atrophy, hypertrophic cardiomyopathy, and diabetes mellitus. 1,4 The onset of FRDA is usually between the ages of 10 and 15 years, leading to wheelchair dependence and premature death by the 4th decade. 4,5 The recent focus on disease-modifying therapies for FRDA has highlighted the need for validated biomarkers of disease progression. 6,7 The current standards to assess FRDA disease severity are the two clinical scales Friedreich's Ataxia Rating Scale (FARS) 8,9 and Scale for the Assessment and Rating of Ataxia (SARA). 10 Based on a body of literature demonstrating the presence of a distal axonopathy and abnormal quantitative sensory thresholds in FRDA, indicative of unmyelinated nerve fiber pathology, 11 we hypothesized that quantification of View this article online at wileyonlinelibrary.com.

show abstract

Section: Study Populationmentioning

confidence: 99%

mentioning

confidence: 99%

Corneal confocal microscopy: Neurologic disease biomarker in Friedreich ataxia

Pagovich

Zhao

et al. 2018

Annals of Neurology

View full text Add to dashboard Cite

show abstract

“…The major cellular consequences of its deficiency include: impairment of iron-sulfur clusters biogenesis, altered cellular iron metabolism with cytosolic iron depletion and mitochondrial iron accumulation, increased oxidative stress, and mitochondrial dysfunction [3,4]. Several therapeutic strategies have expanded rapidly over recent years [5]. Because the success of these therapies for FA is limited [6], there is a need to search for new molecules with beneficial effects on damaged organs in order to ameliorate the quality of life of FA patients.…”

Section: Introductionmentioning

confidence: 99%

Liver Growth Factor (LGF) Upregulates Frataxin Protein Expression and Reduces Oxidative Stress in Friedreich’s Ataxia Transgenic Mice

Calatrava-Ferreras

Gonzalo‐Gobernado

Reimers

et al. 2016

IJMS

View full text Add to dashboard Cite

Friedreich’s ataxia (FA) is a severe disorder with autosomal recessive inheritance that is caused by the abnormal expansion of GAA repeat in intron 1 of FRDA gen. This alteration leads to a partial silencing of frataxin transcription, causing a multisystem disorder disease that includes neurological and non-neurological damage. Recent studies have proven the effectiveness of neurotrophic factors in a number of neurodegenerative diseases. Therefore, we intend to determine if liver growth factor (LGF), which has a demonstrated antioxidant and neuroprotective capability, could be a useful therapy for FA. To investigate the potential therapeutic activity of LGF we used transgenic mice of the FXNtm1MknTg (FXN)YG8Pook strain. In these mice, intraperitoneal administration of LGF (1.6 μg/mouse) exerted a neuroprotective effect on neurons of the lumbar spinal cord and improved cardiac hypertrophy. Both events could be the consequence of the increment in frataxin expression induced by LGF in spinal cord (1.34-fold) and heart (1.2-fold). LGF also upregulated by 2.6-fold mitochondrial chain complex IV expression in spinal cord, while in skeletal muscle it reduced the relation oxidized glutathione/reduced glutathione. Since LGF partially restores motor coordination, we propose LGF as a novel factor that may be useful in the treatment of FA.

show abstract

“…14,15 In these disorders, mitochondrial functions are compromised; however, there is no evidence of CoQ10 deficiency, since levels of CoQ10 are normal in the brains of patients with Parkinson disease 10,11 and in the cerebellum of patients with Friedreich ataxia. 10 Mitochondria are responsible for many important biological functions; therefore, CoQ10 might not be able to rescue mitochondrial defects specific to Parkinson disease or Friedreich ataxia.…”

mentioning

confidence: 99%

“…9 This limitation is even more prominent in the brain because the exogenous CoQ10must be able to cross the blood-brain barrier to effectively treat neurologic disorders; therefore, large doses of CoQ10 (approximately 1200-2400 mg/d) are generally needed to reach the brain. 14,15 From the previous experience of clinical trials of CoQ10, 14 these doses are generally well-tolerated. Moreover, efficacy of the therapy may be increased by the use of ubiquinol, the reduced form of CoQ10, which has greater bioavailability than CoQ10.…”

mentioning

confidence: 99%