Scientific News

The aim of this study is to develop a valid, disease-specific, patient-reported outcome (PRO) measure for adolescents and adults with Friedreich ataxia (FA) for use in therapeutic trials. Semistructured qualitative interviews and a national cross-sectional study of individuals with FA were conducted to determine the most prevalent and burdensome symptoms and symptomatic themes to this population. These symptoms and symptomatic themes were included as questions in the first version of the Friedreich's Ataxia-Health Index (FA-HI). The authors subsequently used factor analysis, beta interviews with 17 individuals with FA, and test-retest reliability assessments with 20 individuals with FA to evaluate, refine, and optimize the FA-HI. Finally, they determined the capability of the FA-HI to differentiate between subgroups of FA participants with varying levels of disease severity. Participants with FA identified 18 symptomatic themes of importance to be included as subscales in the FA-HI. The FA-HI demonstrates high internal consistency and test-retest reliability, and it was identified by participants as highly relevant, comprehensive, and easy to complete. FA-HI total and subscale scores statistically differentiated between subgroups of participants with varying levels of disease burden. Initial evaluation of the FA-HI supports its validity and reliability as a PRO for assessing how individuals with FA feel and function.

Read More Here
 
 

Scientists and pharmaceutical companies are working towards delivering gene therapy for Friedreich ataxia (FRDA). Understanding the views of people with lived experience of FRDA and their parents toward gene therapy is essential to inform trial design and identify potential barriers to participation in clinical trials. The goals of this study were to identify the attitudes towards gene therapy held by individuals with FRDA and parents of individuals with FRDA, and to explore how these may impact future trials for this condition. Audio-recorded, semi-structured, qualitative interviews with nineteen Australians explored experiences of FRDA, knowledge about clinical trials, views on gene therapy including risks and benefits, and potential barriers to participation in trials. Participants included thirteen individuals living with FRDA aged between 15-43 years, and six parents of children with FRDA aged 4-12 years of age. Thematic analysis of the interviews identified six main themes. Findings from this study indicate there is strong desire for information regarding gene therapy in FRDA however the current level of uncertainty around gene therapy makes decision making challenging. The desire to maintain functional status and avoid additional risk of deterioration from an investigational treatment was apparent. Importantly, neurological targets were identified as preferred for gene therapy trials. Further research is required to identify if attitudes and perceptions differ according to geographical location and disease stage.

Read More Here
 
 

The YG8sR mice are Knock-Out (KO) for their murine frataxin gene but contain a human frataxin transgene derived from an FRDA patient with 300 GAA repeats. These mice are used as a FRDA model but even with a low frataxin concentration, their phenotype is mild. The authors aimed to find an optimized mouse model with a phenotype comparable to the human patients to study the impact of therapy on the phenotype. Two mouse models were compared: the YG8sR injected with an AAV. PHP.B coding for a shRNA targeting the human frataxin gene and the YG8-800, a new mouse model with a human transgene containing 800 GAA repeats. Both mouse models were compared to Y47R mice containing nine GAA repeats that were considered healthy mice. Behavior tests (parallel rod floor apparatus, hanging test, inverted T beam, and notched beam test) were carried out from 2 to 11 months and significant differences were noticed for both YG8sR mice injected with an anti-FXN shRNA and the YG8-800 mice compared to healthy mice. In conclusion, YG8sR mice have a slight phenotype, and injecting them with an AAV-PHP.B expressing an shRNA targeting frataxin does increase their phenotype. The YG8-800 mice have a phenotype comparable to the human ataxic phenotype.

Read More Here
 
 

FRDA pathophysiology is characterized by a plethora of metabolic disruptions related to iron metabolism, mitochondrial homeostasis and oxidative stress. Importantly, an impairment of the antioxidant defences exacerbates the oxidative damage. This appears closely associated with the disablement of key antioxidant proteins, such as the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and the mitochondrial superoxide dismutase (MnSOD). The cytokine interferon gamma (IFN-γ) has been shown to increase frataxin expression in FRDA cells and to improve functional deficits in FRDA mice. Currently, IFN-γ represents a potential therapy under clinical evaluation in FRDA patients. Here, we show that IFN-γ induces a rapid expression of Nrf2 and MnSOD in different cell types, including FRDA patient-derived fibroblasts. Our data indicate that IFN-γ signals two separate pathways to enhance Nrf2 and MnSOD levels in FRDA fibroblasts. MnSOD expression increased through an early transcriptional regulation, whereas the levels of Nrf2 are induced by a post-transcriptional mechanism. We demonstrate that the treatment of FRDA fibroblasts with IFN-γ stimulates a non-canonical Nrf2 activation pathway through p21 and potentiates antioxidant responses under exposure to hydrogen peroxide. Moreover, IFN-γ significantly reduced the sensitivity to hydrogen peroxide-induced cell death in FRDA fibroblasts. Collectively, these results indicate the presence of multiple pathways triggered by IFN-γ with therapeutic relevance to FRDA.

Read More Here