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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.


Frataxin deficiency in Friedreich's ataxia is associated with reduced levels of HAX-1, a regulator of cardiomyocyte death and survival

A microarray analysis performed on FRDA patient's lymphoblastoid cells stably reconstituted with frataxin, indicated HS-1-associated protein X-1 (HAX-1) as the most significantly upregulated transcript (FC=+2, P<0.0006). quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) and western blot analysis performed on (I) HEK293 stably transfected with empty vector compared to wild-type frataxin and (II) lymphoblasts from FRDA patients show that low frataxin mRNA and protein expression correspond to reduced levels of HAX-1. Frataxin overexpression and silencing were also performed in the AC16 human cardiomyocyte cell line. HAX-1 protein levels are indeed regulated through frataxin modulation. Moreover, correlation between frataxin and HAX-1 was further evaluated in peripheral blood mononuclear cells (PBMCs) from FRDA patients and from non-related healthy controls. A regression model for frataxin which included HAX-1, group membership and group* HAX-1 interaction revealed that frataxin and HAX-1 are associated both at mRNA and protein levels. Additionally, a linked expression of FXN, HAX-1 and antioxidant defense proteins MnSOD and Nrf2 was observed both in PBMCs and AC16 cardiomyocytes. This study suggests that HAX-1 could be considered as a potential biomarker of cardiac disease in FRDA and the evaluation of its expression might provide insights into its pathogenesis as well as improving risk stratification strategies.

Read the entire article HERE

Health related quality of life in Friedreich Ataxia in a large heterogeneous cohort

This study assessed the Health Related Quality of Life (HRQOL) of individuals with Friedreich Ataxia (FRDA) through responses to HRQOL questionnaires. The SF-36, a generic HRQOL instrument, and symptom specific scales examining vision, fatigue, pain and bladder function were administered to individuals with FRDA and analyzed by comparison with disease features. Multiple linear regression models were used to study independent effects of genetic severity and age. Assessments were performed at baseline then intermittently after that. Subjects were on average young adults. For the SF36, the subscale with the lowest HRQOL score was the physical function scale, while the emotional well-being score was the highest. The physical function scale correlated with age of onset, duration, and subject age. In assessment of symptom specific scales, bladder control scores (BLCS) correlated with duration and age, while impact of visual impairment scores (IVIS) correlated with duration. In linear regression models, the BLCS, Pain Effect Score, and IVIS scores were predicted by age and GAA length; modified fatigue impact scale scores were predicted only by GAA length. Physical function and role limitation scores declined over time. No change was seen over time in other SF-36 subscores. Symptom specific scales also worsened over time, most notably the IVIS and BLCS. The SF-36 and symptom specific scales capture dysfunction in FRDA in a manner that reflects disease status. HRQOL dysfunction was greatest on physically related scales; such scales correlated with disease duration, indicating that they worsen with progressing disease.

Read the entire article HERE

Multiple mechanisms underpin cerebral and cerebellar white matter deficits in Friedreich ataxia: The IMAGE-FRDA study

This study examined the relative sensitivity and relationship between multiple white matter indices in Friedreich ataxia to more richly characterize disease expression and infer possible mechanisms underlying the observed white matter abnormalities. Diffusion-tensor, magnetization transfer, and T1-weighted structural images were acquired from 31 individuals with Friedreich ataxia and 36 controls. Six white matter indices were extracted: fractional anisotropy, diffusivity (mean, axial, radial), magnetization transfer ratio (microstructure), and volume (macrostructure). For each index, whole-brain voxel-wise between-group comparisons and correlations with disease severity, onset age, and gene triplet-repeat length were undertaken. Correlations between pairs of indices were assessed in the Friedreich ataxia cohort. Spatial similarities in the voxel-level pattern of between-group differences across the indices were also assessed. Microstructural abnormalities were maximal in cerebellar and brainstem regions, but evident throughout the brain, while macroscopic abnormalities were restricted to the brainstem. Poorer microstructure and reduced macrostructural volume correlated with greater disease severity and earlier onset, particularly in peri-dentate nuclei and brainstem regions. Microstructural and macrostructural abnormalities were largely independent. Reduced fractional anisotropy was most strongly associated with axial diffusivity in cerebral tracts, and magnetization transfer in cerebellar tracts. Multiple mechanisms likely underpin white matter abnormalities in Friedreich ataxia, with differential impacts in cerebellar and cerebral pathways.

Read the entire article HERE

Large-scale contractions of Friedreich's ataxia GAA repeats in yeast occur during DNA replication due to their triplex-forming ability

In somatic tissues of Friedreich's ataxia (FRDA) patients, (GAA)n repeat tracts are highly unstable, with contractions more common than expansions. The authors describe an experimental system to characterize GAA repeat contractions in yeast and to conduct a genetic analysis of this process. The study found that large-scale contraction is a one-step process, resulting in a median loss of ∼60 triplet repeats. This genetic analysis revealed that contractions occur during DNA replication, rather than by various DNA repair pathways. Repeats contract in the course of lagging-strand synthesis: The processivity subunit of DNA polymerase δ, Pol32, and the catalytic domain of Rev1, a translesion polymerase, act together in the same pathway to counteract contractions. Accumulation of single-stranded DNA (ssDNA) in the lagging-strand template greatly increases the probability that (GAA)n repeats contract, which in turn promotes repeat instability in rfa1, rad27, and dna2 mutants. Finally, by comparing contraction rates for homopurine-homopyrimidine repeats differing in their mirror symmetry, we found that contractions depend on a repeat's triplex-forming ability. The authors propose that accumulation of ssDNA in the lagging-strand template fosters the formation of a triplex between the nascent and fold-back template strands of the repeat. Occasional jumps of DNA polymerase through this triplex hurdle, result in repeat contractions in the nascent lagging strand.

Read the entire article HERE

MDA Awards Venture Philanthropy Funding of More Than $1M to AavantiBio to Develop Gene-Targeting Therapy for Friedreich's Ataxia

NEW YORK and GAINESVILLE, Fla., Jan. 13, 2020 -- The Muscular Dystrophy Association (MDA) and AavantiBio, a biotechnology company developing a gene-targeting therapy for Friedreich's ataxia (FA), today announced the award of MDA Venture Philanthropy (MVP) funding totaling $1,076,232 to advance AavantiBio's phase 2 clinical trial of a gene-replacement therapy for the disease. MVP is MDA's drug development program, which is exclusively focused on funding the discovery and clinical application of treatments and cures for neuromuscular disorders. MVP evaluates and makes targeted investments in for-profit and not-for-profit companies and academics developing therapeutics.

Read the entire Press Release HERE

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