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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.



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

Large Interruptions of GAA Repeat Expansion Mutations in Friedreich Ataxia Are Very Rare

In Friedreich ataxia the deficiency of frataxin protein leads to progressive mitochondrial dysfunction, oxidative stress, and cell death, with the main affected sites being the large sensory neurons of the dorsal root ganglia and the dentate nucleus of the cerebellum. The GAA repeat expansions may be pure (GAA)n in sequence or may be interrupted with regions of non-GAA sequence. This is the first large-scale study of FRDA patient DNA samples to determine the frequency of large interruptions in GAA repeat expansions. The group investigated a panel of 245 Friedreich ataxia patient and carrier DNA samples and showed that the vast majority (97.8%) of Friedreich ataxia GAA repeat expansion samples do not contain significant sequence changes, indicating that they are primarily pure GAA repeats. These results show for the first time that large interruptions in the GAA repeats are very rare.

Read the entire article HERE

Depressive symptoms in Friedreich ataxia

The aim of this study was to study the presence and the profile of depressive symptoms in FRDA and their relationship with demographic-disease variables and cognitive processing speed. The group studied 57 patients with a diagnosis of FRDA using the Beck Depression Inventory-II (BDI) to assess symptoms of depression. Speed of information processing was measured with a Choice Reaction time task. The mean BDI score for patients was significantly higher than the mean score in the general population. Twenty one percent of participants scored in the moderate/severe range. A Cognitive-Affective score and a Somatic-Motivational score was calculated for each patient. Patients' scores in both dimensions were significantly higher than the scores in the general population. Demographic and disease variables were not related with symptoms of depression, except for severity of ataxia. Depressive symptoms predict cognitive reaction times. The greater proportion of variance was explained by the Cognitive-Affective dimension. This data show that both somatic-motivational and cognitive affective symptoms of depression are frequent in individuals with FRDA. In addition, depressive symptoms may influence cognition, especially, the cognitive and affective symptoms.

Read the entire article HERE

FAST-1 antisense RNA epigenetically alters FXN expression

Friedreich ataxia (FRDA) is a multisystem genetic disorder caused by GAA repeat expansion mutations within the FXN gene, resulting in heterochromatin formation and deficiency of frataxin protein. Elevated levels of the FXN antisense transcript (FAST-1) have previously been detected in FRDA. To investigate the effects of FAST-1 on the FXN gene expression, this group looked at effects of FAST-1 in non-FRDA cell lines and in FRDA fibroblast cells. They observed decreased FXN expression in each FAST-1 overexpressing cell type compared to control cells and found that FAST-1 overexpression is associated with both CCCTC-Binding Factor (CTCF) depletion and heterochromatin formation at the 5'UTR of the FXN gene. Knocking down FAST-1 in FRDA cells significantly increased FXN expression. The effects of FAST-1 expression on the FXN locus suggest a direct role for FAST-1 in the FRDA molecular disease mechanism and support the hypothesis that inhibition of FAST-1 may be a potential approach for FRDA therapy.

Read the entire article HERE

Characterization of a new N-terminally acetylated extra-mitochondrial isoform of frataxin in human erythrocytes

Frataxin is a highly conserved protein encoded by the frataxin (FXN) gene. The full-length 210-amino acid form of protein frataxin (1-210; isoform A) expressed in the cytosol of cells rapidly gets moved to the mitochondria, where it is converted to the mature form (81-210). Mature frataxin (81-210) is a critically important protein because it facilitates the assembly of mitochondrial iron-sulfur cluster protein complexes such as aconitase, lipoate synthase, and succinate dehydrogenases. Decreased expression of frataxin protein is responsible for Friedreich's ataxia. The mitochondrial form of frataxin has long been thought to be present in red blood cells even though they lack mitochondria. This paper shows that frataxin in red blood cells is a novel form of frataxin (called isoform E) with 135-amino acids and an N-terminally acetylated methionine residue. There is three times more isoform E in red blood cells from the whole blood of healthy volunteers compared to the mature mitochondrial frataxin present in other blood cells. Isoform E lacks a mitochondrial targeting sequence and so is distributed to both cytosol and the nucleus when expressed in cultured cells. When extra-mitochondrial frataxin isoform E is expressed in HEK 293 cells, it is converted to a shorter isoform identical to the mature frataxin found in mitochondria, which raises the possibility that it is involved in disease etiology. The ability to specifically quantify extra-mitochondrial and mitochondrial isoforms of frataxin in whole blood will make it possible to readily follow the natural history of diseases such as Friedreich's ataxia and monitor the efficacy of therapeutic interventions.

Read the entire article HERE

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