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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.



Phosphodiesterase Inhibitors Revert Axonal Dystrophy in Friedreich's Ataxia Mouse Model

A major feature of FRDA is frataxin deficiency, with the loss of large sensory neurons of the dorsal root ganglia (DRG) undergoing dying-back neurodegeneration. This group used isolated DRGs from a FRDA mouse model and control mice for a proteomic study and a primary culture of sensory neurons from DRG to test novel pharmacological strategies. They found a decreased expression of electron transport chain proteins, the oxidative phosphorylation system and antioxidant enzymes, confirming a clear impairment in mitochondrial function and an oxidative stress-prone phenotype. The proteomic profile also showed a decreased expression in Ca2+ signaling related proteins and G protein-coupled receptors . These receptors modulate intracellular cAMP/cGMP and Ca2+ levels. Treatment of frataxin-deficient sensory neurons with phosphodiesterase (PDE) inhibitors was able to restore improper cytosolic Ca2+ levels and revert the axonal dystrophy found in DRG neurons of YG8R mice. In conclusion, the present study shows the effectiveness of PDE inhibitors against axonal degeneration of sensory neurons from YG8R mice. This suggests that PDE inhibitors should be looked at as a future FRDA treatment.

Read the entire article HERE

Heart disease in Friedreich's ataxia

Friedreich's ataxia (FRDA), which occurs in 1/50000 live births, is the most prevalent inherited neuromuscular disorder. Nearly all FRDA patients develop cardiomyopathy at some point in their lives. The clinical manifestations of FRDA include ataxia of the limbs and trunk, dysarthria, diabetes mellitus, and cardiac diseases. However, the broad clinical spectrum makes FRDA difficult to identify. The diagnosis of FRDA is based on the presence of suspicious clinical factors, the use of the Harding criteria and, more recently, the use of genetic testing for identifying the expansion of a triplet nucleotide sequence. FRDA is linked to a defect in the mitochondrial protein frataxin; an epigenetic alteration interferes with the folding of this protein, causing a relative deficiency of frataxin in affected patients. Frataxins are small essential proteins whose deficiency causes a range of metabolic disturbances, including oxidative stress, iron-sulfur cluster deficits, and defects in heme synthesis, sulfur amino acid metabolism, energy metabolism, stress responses, and mitochondrial function. The cardiac involvement seen in FRDA is a consequence of mitochondrial proliferation as well as the loss of contractile proteins and the subsequent development of myocardial fibrosis. The walls of the left ventricle become thickened, and different phenotypic manifestations are seen, including concentric or asymmetric hypertrophy and (less commonly) dilated cardiomyopathy. Dilated cardiomyopathy and arrhythmia are associated with mortality in patients with FRDA, whereas hypertrophic cardiomyopathy is not. Systolic function tends to be low-normal in FRDA patients, with an acute decline at the end of life. However, the literature includes only a few long-term prospective studies of cardiac progression in FRDA, and the cause of death is often attributed to heart failure and arrhythmia postmortem. Cardiomyopathy tends to be correlated with the clinical neurologic age of onset and the nucleotide triplet repeat length (i.e., markers of phenotypic disease severity) rather than the duration of disease or the severity of neurologic symptoms. As most patients are wheelchair-users within 15 years of diagnosis, the clinical determination of cardiac involvement is often complicated by comorbidities. Researchers are currently testing targeted therapies for FRDA, and a centralized database, patient registry, and natural history study have been launched to support these clinical trials. The present review discusses the pathogenesis, clinical manifestations, and spectrum of cardiac disease in FRDA patients and then introduces gene-targeted and pathology-specific therapies as well as screening guidelines that should be used to monitor cardiac disease in this mitochondrial disorder.

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Neurocrine Biosciences and Voyager Therapeutics Form Strategic Development and Commercialization Collaboration for Parkinson’s Disease and Friedreich’s Ataxia

SAN DIEGO and CAMBRIDGE, Mass., Jan. 29, 2019 (GLOBE NEWSWIRE) -- Neurocrine Biosciences, Inc. (NASDAQ: NBIX) and Voyager Therapeutics, Inc. (NASDAQ: VYGR), today announced the formation of a strategic collaboration focused on the development and commercialization of Voyager's gene therapy programs, VY-AADC for Parkinson's disease and VY-FXN01 for Friedreich's ataxia, as well as rights to two programs to be determined. This collaboration combines Neurocrine Biosciences’ expertise in neuroscience, drug development and commercialization with Voyager’s innovative gene therapy programs targeting severe neurological diseases.

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OGTT is recommended for glucose homeostasis assessments in Friedreich ataxia

Diabetes is a common complication of Friedreich ataxia, requiring sensitive diagnostic methods. Here, we compared the performance of different tests that assess glucose tolerance, insulin sensitivity, and β-cell function in Friedreich ataxia patients, heterozygous FXN mutation carriers and controls. We find that diabetes is underdiagnosed with fasting glucose alone. The oral glucose tolerance test (OGTT) provides 1.2- to 3.5-fold more diagnoses of impaired glucose homeostasis and diabetes, and adequately measures insulin sensitivity, insulin secretion, and β-cell function. Clinicians in charge of Friedreich ataxia patients and researchers should incorporate the OGTT as an accurate diagnostic and research tool.

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Ferroptosis as a novel therapeutic target for Friedreich's ataxia

Friedreich ataxia (FRDA) is a progressive neuro- and cardio-degenerative disorder characterized by ataxia, sensory loss, and hypertrophic cardiomyopathy. In most cases, the disorder is caused by GAA repeat expansions in the first introns of both alleles of the FXN gene, resulting in decreased expression of the encoded protein, frataxin. Frataxin localizes to the mitochondrial matrix and is required for iron-sulfur-cluster biosynthesis. Decreased expression of frataxin is associated with mitochondrial dysfunction, mitochondrial iron accumulation, and increased oxidative stress. Ferropotosis is a recently identified pathway of regulated, iron-dependent cell death, which is biochemically distinct from apoptosis. This group evaluated whether there is evidence for ferroptotic pathway activation in cellular models of FRDA. They found that primary patient-derived fibroblasts, murine fibroblasts with FRDA-associated mutations, and murine fibroblasts in which a repeat expansion had been introduced (KIKO) were more sensitive than normal control cells to erastin, a known ferroptosis inducer. We also found that the ferroptosis inhibitors SRS11-92 and Fer-1, used at 500 nM, were efficacious in protecting human and mouse cellular models of FRDA treated with ferric ammonium citrate (FAC) and an inhibitor of glutathione synthesis (BSO), whereas caspase-3 inhibitors failed to show significant biological activity. Cells treated with FAC and BSO consistently showed decreased glutathione-dependent peroxidase activity and increased lipid peroxidation, both hallmarks of ferroptosis. Finally, the ferroptosis inhibitor SRS11-92 decreased the cell death associated with frataxin knockdown in healthy human fibroblasts. Taken together, these data suggest that ferroptosis inhibitors may have therapeutic potential in FRDA.

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