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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.

Ataxia: Hope starts with measurement

FARA and AFAF (our advocacy partner in France) awarded a research grant, from rideATAXIA raised funds, to Dr. Corben and colleagues to develop and test a digital spoon as a way to measure upper limb function in FA. With that original grant award the team demonstrated that this device was able to measure function reliability and accurately in individuals with mild and severe symptoms of ataxia. With this new funding they can take this device and other devices for measuring ataxia to the clinic so that we have improved tools for monitoring outcomes and treatment responses in our natural history study and clinical trials.

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Friedreich Ataxia: current state-of-the-art, and future prospects for mitochondrial-focused therapies

A body of literature has been focused on the attempts to counteract frataxin deficiency and the consequent iron imbalance, in order to mitigate the disease-associated prooxidant state and clinical course. The present mini review is aimed at evaluating the basic and clinical reports on the roles and the use of a set of iron chelators, antioxidants and some cofactors involved in the key mitochondrial functions. Extensive literature has focused on the protective roles of iron chelators, coenzyme Q10 and analogs, and vitamin E, altogether with varying outcomes in clinical studies. Other studies have suggested mitoprotective roles for other mitochondrial cofactors, involved in Krebs cycle, such as alpha-lipoic acid and carnitine, involved in acyl transport across the mitochondrial membrane. A body of evidence points to the strong antioxidant properties of these cofactors, and to their potential contribution in mitoprotective strategies in Friedreich's Ataxia clinical evolution. Thus, the authors suggest the rationale for planning combination strategies based on the three mitochondrial cofactors and of some antioxidants and iron binders as mitoprotective cocktails in FRDA patients, calling attention to clinical practitioners of the importance to implement clinical trials.

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Frataxin gene editing rescues Friedreich's ataxia pathology in dorsal root ganglia organoid-derived sensory neurons

In this study, the authors generate dorsal root ganglia organoids (DRG organoids) by in vitro differentiation of human iPSCs. Bulk and single-cell RNA sequencing show that DRG organoids present a transcriptional signature similar to native DRGs and display the main peripheral sensory neuronal and glial cell subtypes. Furthermore, when co-cultured with human intrafusal muscle fibers, DRG organoid sensory neurons contact their peripheral targets and reconstitute the muscle spindle proprioceptive receptors. FRDA DRG organoids model some molecular and cellular deficits of the disease that are rescued when the entire FXN intron 1 is removed, and not with the excision of the expanded GAA tract. These results strongly suggest that removal of the repressed chromatin flanking the GAA tract might contribute to rescue FXN total expression and fully revert the pathological hallmarks of FRDA DRG neurons.

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Inherited Cerebellar Ataxias: 5-Year Experience of the Irish National Ataxia Clinic

Establishing a molecular diagnosis in patients with progressive ataxia is often challenging due to significant genetic and clinical heterogeneity and requires a methodical approach with expert clinical evaluation and investigations. This study describes the 5-year experience of the National Ataxia Clinic (NAC), Ireland. All adults with ataxia attending the NAC between 2014 and 2019 were evaluated. All individuals underwent detailed clinical assessment and investigations including, where appropriate, genetic testing using next-generation sequencing. For all patients, acquired causes were ruled out. A total of 254 patients from 196 families were assessed; with growth of the clinic cohort by 82% from 133 to 242 over the 5-year period. The underlying genetic cause was identified in 128/196 probands (65.3%). The detection rate for repeat expansion disorder gene testing was 47.7% (82/172) and using NGS gene panel, a genetic diagnosis was obtained in 30/84 (35.7%). Whole exome sequencing identified the molecular diagnosis in 4/20 (20%), and whole genome sequencing provided genetic diagnosis in 1/5 (20%). The commonest diagnosis was Friedreich's ataxia (68/128, 53.1%). SPG7-associated ataxia was the second most common diagnosis (21/128, 16.4%), followed by ANO10-associated spastic ataxia, ataxia telangiectasia (AT), and other rarer phenotypes. These results highlight that careful clinical phenotyping in a dedicated ataxia clinic is crucial for appropriate genetic testing in selected patients in a timely manner. Advanced genetic testing has significantly improved the diagnostic yield in patients with suspected genetic ataxia and should be considered in all individuals with negative repeat expansion testing.

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Atypical structures of GAA/TTC trinucleotide repeats underlying Friedreich's ataxia: DNA triplexes and RNA/DNA hybrids

Expansion of the GAA/TTC repeats in the first intron of the FXN gene causes Friedreich's ataxia. Non-canonical structures are linked to this expansion. DNA triplexes and R-loops are believed to arrest transcription, which results in frataxin deficiency and eventual neurodegeneration. This study presents a systematic in silico characterization of the possible DNA triplexes that could be assembled with GAA and TTC strands; the two hybrid duplexes [r(GAA):d(TTC) and d(GAA):r(UUC)] in an R-loop; and three hybrid triplexes that could form during bidirectional transcription when the non-template DNA strand bonds with the hybrid duplex (collapsed R-loops, where the two DNA strands remain antiparallel). For both Y·R:Y and R·R:Y DNA triplexes, the parallel third strand orientation is more stable; both parallel and antiparallel protonated d(GA+A)·d(GAA):d(TTC) triplexes are stable. Apparent contradictions in the literature about the R·R:Y triplex stability is probably due to lack of molecular resolution, since shifting the third strand by a single nucleotide alters the stability ranking. In the collapsed R-loops, antiparallel d(TTC+)·d(GAA):r(UUC) is unstable, while parallel d(GAA)·r(GAA):d(TTC) and d(GA+A)·r(GAA):d(TTC) are stable. In addition to providing new structural perspectives for specific therapeutic aims, these results contribute to a systematic structural basis for the emerging field of quantitative R-loop biology.

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