New and Emerging Drug and Gene Therapies for Friedreich Ataxia

CNS Drugs, Journal Year: 2024, Volume and Issue: 38(10), P. 791 - 805

Published: Aug. 8, 2024

The life shortening nature of Friedreich Ataxia (FRDA) demands the search for therapies that can delay, stop or reverse its relentless trajectory. This review provides a contemporary position drug and gene FRDA currently in phase 1 clinical trials beyond. Despite significant scientific advances specificity both compounds targets developed investigated, challenges remain advancement treatments limited recruitment population. Currently focus on reducing oxidative stress improving mitochondrial function, modulating frataxin controlled metabolic pathways replacement editing. Approval omaveloxolone, first treatment individuals with aged 16 years over, has created much excitement those living care them. process approval omaveloxolone by US Food Drug Administration highlighted importance sensitive outcome measures role data from natural history studies.

Language: Английский

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A promising mouse model for Friedreich Ataxia progressing like human patients

Behavioural Brain Research, Journal Year: 2022, Volume and Issue: 436, P. 114107 - 114107

Published: Sept. 8, 2022

Language: Английский

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Lipid nanoparticle (LNP) mediated mRNA delivery in neurodegenerative diseases

Journal of Controlled Release, Journal Year: 2025, Volume and Issue: unknown, P. 113641 - 113641

Published: March 1, 2025

Language: Английский

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Glial cell activation precedes neurodegeneration in the cerebellar cortex of the YG8–800 murine model of Friedreich ataxia

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 200, P. 106631 - 106631

Published: Aug. 6, 2024

Friedreich ataxia is a hereditary neurodegenerative disorder resulting from reduced levels of the protein frataxin due to an expanded GAA repeat in FXN gene. This deficiency causes progressive degeneration specific neuronal populations cerebellum and consequent loss movement coordination equilibrium, which are some main symptoms observed affected individuals. Like other diseases, previous studies suggest that glial cells could be involved process disease progression patients with ataxia. In this work, we followed characterized changes cerebellar cortex latest version humanized mouse model, YG8–800 (Fxnnull:YG8s(GAA)>800), carries human transgene containing >800 repeats. Comparative analyses behavioral, histopathological, biochemical parameters were conducted between control strain Y47R mice at different time points. Our findings revealed exhibit ataxic phenotype by poor motor coordination, decreased body weight, atrophy, loss, synaptic proteins. Additionally, early activation cells, predominantly astrocytes microglia, was preceding degeneration, as increased expression key proinflammatory cytokines downregulation neurotrophic factors. Together, our results show model exhibits stronger than experimental murine models, reliably recapitulating features humans. Accordingly, represent valuable tool for studying molecular mechanisms preclinical evaluation possible therapies.

Language: Английский

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A natural history study to track brain and spinal cord changes in individuals with Friedreich’s ataxia: TRACK-FA study protocol

PLoS ONE, Journal Year: 2022, Volume and Issue: 17(11), P. e0269649 - e0269649

Published: Nov. 21, 2022

Introduction Drug development for neurodegenerative diseases such as Friedreich’s ataxia (FRDA) is limited by a lack of validated, sensitive biomarkers pharmacodynamic response in affected tissue and disease progression. Studies employing neuroimaging measures to track FRDA have thus far been their small sample sizes follow up. TRACK-FA, longitudinal, multi-site, multi-modal natural history study, aims address these shortcomings enabling better understanding underlying pathology identifying sensitive, clinical trial ready, FRDA. Methods 200 individuals with 104 control participants will be recruited across seven international study sites. Inclusion criteria genetically confirmed involves, age onset ≤ 25 years, Ataxia Rating Scale (FARS) functional staging score 5, total modified FARS (mFARS) 65 upon enrolment. The cohort matched the age, sex, handedness, years education. Participants evaluated at three visits over two years. Each visit comprises harmonized multimodal Magnetic Resonance Imaging (MRI) Spectroscopy (MRS) scan brain spinal cord; clinical, cognitive, mood speech assessments collection blood sample. Primary outcome measures, informed previous studies, include of: cord morphometry, microstructure (measured using diffusion MRI), iron accumulation (using Quantitative Susceptibility Mapping) biochemistry MRS). Secondary exploratory cognitive biomarkers. Discussion Prioritising immediate areas need, TRACK-FA deliver set trial-ready accelerate drug discovery efforts understand trajectory. Once potential can used measure efficacy new therapeutics forestalling Clinical registration ClinicalTrails.gov Identifier: NCT04349514 .

Language: Английский

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Expression and processing of mature human frataxin after gene therapy in mice

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: April 10, 2024

Abstract Friedreich’s ataxia is a degenerative and progressive multisystem disorder caused by mutations in the highly conserved frataxin (FXN) gene that results FXN protein deficiency mitochondrial dysfunction. While therapy approaches are promising, consistent induction of therapeutic expression sub-toxic has proven challenging, numerous being tested animal models. (hFXN humans, mFXN mice) proteolytically modified mitochondria to produce mature FXN. However, unlike endogenous hFXN, further processed into N-terminally truncated, extra-mitochondrial forms unknown function. This study assessed exogenous hFXN levels heart liver C57Bl/6 mice 7–10 months after intravenous administration recombinant adeno-associated virus encoding (AAVrh.10hFXN) examined potential for truncation mice. AAVrh.10hFXN induced dose-dependent liver. Interestingly, was truncated forms, but found at lower than hFXN. truncations were different positions mFXN. mouse approximated levels. These suggest can likely induce

Language: Английский

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Emerging therapies in hereditary ataxias

Trends in Molecular Medicine, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 1, 2024

Language: Английский

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Treatment with ROS detoxifying gold quantum clusters alleviates the functional decline in a mouse model of Friedreich ataxia

Science Translational Medicine, Journal Year: 2021, Volume and Issue: 13(607)

Published: Aug. 18, 2021

Gold quantum clusters are therapeutic in preclinical models of Friedreich ataxia.

Language: Английский

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Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations

Cellular and Molecular Life Sciences, Journal Year: 2022, Volume and Issue: 79(2)

Published: Jan. 17, 2022

Abstract Friedreich Ataxia (FA) is a rare neuro-cardiodegenerative disease caused by mutations in the frataxin ( FXN ) gene. The most prevalent mutation GAA expansion first intron of gene causing decreased expression. Some patients present one allele and missense other allele. One these mutations, FXNI154F, was reported to result content mature increased presence an insoluble intermediate proteoform cellular models. By introducing this into murine Fxn (I151F, equivalent human I154F) we have now analyzed consequences pathological point vivo. We observed that I151F homozygous mice low levels all tissues, with no evidence proteoforms. Moreover, they display neurological deficits resembling those FA patients. Biochemical analysis heart, cerebrum cerebellum revealed components from OXPHOS complexes I II, aconitase activity, alterations antioxidant defenses. These mitochondrial are more marked nervous system than precede appearance symptoms, similar conclude primary mechanism underlying deficiency, like carrying expansions. Therefore, I154F would benefit replacement therapies. Furthermore, our results also show mouse excellent tool for analyzing tissue-specific deficiency testing new

Language: Английский

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Patient-derived iPSC models of Friedreich ataxia: a new frontier for understanding disease mechanisms and therapeutic application

Translational Neurodegeneration, Journal Year: 2023, Volume and Issue: 12(1)

Published: Sept. 20, 2023

Abstract Friedreich ataxia (FRDA) is a rare genetic multisystem disorder caused by pathological GAA trinucleotide repeat expansion in the FXN gene. The numerous drawbacks of historical cellular and rodent models FRDA have difficulty performing effective mechanistic translational studies to investigate disease. recent discovery subsequent development induced pluripotent stem cell (iPSC) technology provides an exciting platform enable enhanced disease modelling for diseases. Utilising iPSCs, researchers created phenotypically relevant previously inaccessible FRDA. These molecular mechanisms underlying GAA-induced pathology, as well providing tool screening testing novel disease-modifying therapies. This review explores how use iPSCs study has developed over past decade, discussing enormous therapeutic potentials iPSC-derived models, their current limitations future direction within field research. Graphical abstract

Language: Английский

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