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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.



Drug repositioning screening identifies etravirine as a potential therapeutic for friedreich's ataxia

Given that levels of residual frataxin critically affect disease severity, the main goal of a specific therapy for Friedreich's ataxia is to increase frataxin levels. With the aim to accelerate the development of a new therapy for Friedreich's ataxia, this group took a drug repositioning approach to identify market-available drugs able to increase frataxin levels. Using a cell-based reporter assay to monitor variation in frataxin amount, they performed high-throughput screening of a library containing 853 U.S. Food and Drug Administration-approved drugs. Among the potentially interesting candidates isolated from the screening, they focused their attention on etravirine, an antiviral drug currently in use as an anti-human immunodeficiency virus therapy. In this paper, they show that etravirine can promote a significant increase in frataxin levels in cells derived from Friedreich's ataxia patients, by enhancing frataxin messenger RNA translation. Importantly, frataxin accumulation in treated patient cell lines is comparable to frataxin levels in unaffected carrier cells, suggesting that etravirine could be therapeutically relevant. Indeed, etravirine treatment restores the activity of the iron-sulphur cluster containing enzyme aconitase and confers resistance to oxidative stress in cells derived from Friedreich's ataxia patients. Considering its safety profile along with its ability to increase frataxin levels and correct some of the disease-related defects, etravirine represents a promising candidate as a therapeutic for Friedreich's ataxia.

Read the entire article HERE

Differences in the determinants of right ventricular and regional left ventricular long-axis dysfunction in Friedreich ataxia

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative condition which also has effects on the heart. In 96% of affected individuals FRDA is due to homozygosity of a GAA repeat expansion in intron 1 of the frataxin (FXN) gene. The number of GAA repeats have been shown to relate to disease severity in FRDA, this thought to be via an inverse relationship of GAA repeat number and cellular frataxin levels. This group investigated the effects of FRDA on regional long axis function of the left and right ventricles, and also the relationship of long axis systolic (s`) and early diastolic (e`) peak velocities with GAA repeat number on the shorter (GAA1) and longer FXN alleles (GAA2). The study group of 78 adult subjects (age 32±9 years) with FRDA and normal left ventricular (LV) ejection fraction were compared to 54 healthy control subjects of similar age, sex and body size. Tissue Doppler imagin g (TDI) signals were recorded at the mitral annulus for measurement of s` and e`of the septal, lateral, anterior and inferior walls and at the tricuspid annulus for measurement of right ventricular (RV) s` and e`. All the regional LV s` and e`, and both RV s` and RV e`, were lower in individuals with FRDA compared to controls (p<0.001 for all). On multivariate analysis, which included LV septal wall thickness (SWT), RV s` and RV e` were both inversely correlated with GAA1 (β = -0.32 & -0.33, respectively, p = 0.01), but not with GAA2, whereas anterior and lateral s` were both inversely correlated with GAA2 (β = -0.25 and β = -0.28, p = 0.02) but not with GAA1. Increasing SWT was the most consistent LV structural correlate of lower s` and e`, whereas age was a consistent inverse correlate of e` but not of s`.There are generalized abnormalities of both LV regional and RV long axis function in FRDA, but there are also regional differences in the association of this dysfunction with the smaller and larger GAA repeats in the FXN gene.

Read the entire article HERE

GRP75 overexpression rescues frataxin deficiency and mitochondrial phenotypes in Friedreich Ataxia cellular models

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein crucial for iron-sulphur cluster biogenesis and ATP production. Currently there is no therapy to slow down the progression of FRDA. Recent evidence indicates that posttranslational regulation of residual frataxin levels can rescue some of the functional deficit of FRDA, raising the possibility of enhancing levels of residual frataxin as a treatment for FRDA. Here, we present evidence that mitochondrial molecular chaperone GRP75, also known as mortalin/mthsp70/PBP74, directly interacts with frataxin both in vivo in mouse cortex and in vitro in cortical neurons. Overexpressing GRP75 increases the levels of both wild-type frataxin and clinically relevant missense frataxin variants in HEK293 cells while clinical GRP75 variants such as R126W, A476T and P509S impair the binding of GRP75 with frataxin and the effect of GRP75 on frataxin levels. In addition, GRP75 overexpression rescues frataxin deficiency and abnormal cellular phenotypes such as the abnormal mitochondrial network and decreased ATP levels in FRDA patient-derived cells. The effect of GRP75 on frataxin might be in part mediated by the physical interaction between GRP75 and mitochondrial processing peptidase (MPP), which makes frataxin more accessible to MPP. As GRP75 levels are decreased in multiple cell types of FRDA patients, restoring GRP75 might be effective in treating both typical FRDA patients with two GAA repeat expansions and compound heterozygous patients with point mutations.

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Transcriptional profiling of isogenic Friedreich ataxia neurons and effect of an HDAC inhibitor on disease signatures

Friedreich ataxia (FRDA) is a neurodegenerative disorder caused by transcriptional silencing of the FXN gene, resulting in loss of the essential mitochondrial protein frataxin. Based on the knowledge that a GAA•TTC repeat expansion in the first intron of FXN induces heterochromatin, this group previously showed that 2-aminobenzamide-type histone deacetylase inhibitors (HDACi) increase FXN mRNA levels in induced pluripotent stem cell (iPSC)-derived FRDA neurons and in circulating lymphocytes from patients after HDACi oral administration. How the reduced expression of frataxin leads to neurological and other systemic symptoms in FRDA patients remains unclear. Similar to other triplet-repeat disorders, it is unknown why FRDA affects only specific cell types, primarily the large sensory neurons of the dorsal root ganglia and cardiomyocytes. The combination of iPSC technology and genome-editing techniques offers the unique possibility to address these questions in a relevant cell model of FRDA, obviating confounding effects of variable genetic backgrounds. Here, using "scarless" gene-editing methods, they created isogenic iPSC lines that differ only in the length of the GAA·TTC repeats. To uncover the gene expression signatures due to the GAA·TTC repeat expansion in FRDA neuronal cells and the effect of HDACi on these changes, they performed RNA-seq-based transcriptomic analysis of iPSC-derived central nervous system (CNS) and isogenic sensory neurons. They found that cellular pathways related to neuronal function, regulation of transcription, extracellular matrix organization and apoptosis are affected by frataxin loss in neurons of the CNS and peripheral nervous system and that these changes are partially restored by HDACi treatment.

Read the entire article HERE

Correction of half the cardiomyocytes fully rescue Friedreich Ataxia mitochondrial cardiomyopathy through cell-autonomous mechanisms

Cardiac failure constitutes the main cause of premature death in FA. While AAV-mediated cardiac gene therapy was shown to fully reverse the cardiac and mitochondrial phenotype in mouse models, this was achieved at high dose of vector resulting in the transduction of almost all cardiomyocytes, a dose and biodistribution that is unlikely to be replicated in clinic. The purpose of this study was to define the minimum vector biodistribution corresponding to the therapeutic threshold, at different stages of the disease progression. Correlative analysis of vector cardiac biodistribution, survival, cardiac function and biochemical hallmarks of the disease revealed that full rescue of the cardiac function was achieved when only half of the cardiomyocytes were transduced. In addition, meaningful therapeutic effect was achieved with as little as 30% transduction coverage. This therapeutic effect was mediated through cell-autonomous mechanisms for mitochondria homeostasis, although a significant increase in survival of uncorrected neighboring cells was observed. Overall, this study identifies the biodistribution thresholds and the underlying mechanisms conditioning the success of cardiac gene therapy in Friedreich Ataxia and provides guidelines for the development of the clinical administration paradigm.

Read the entire article HERE

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