A wearable motion capture suit and machine learning predict disease progression in Friedreich’s ataxia

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(1), P. 86 - 94

Published: Jan. 1, 2023

Abstract Friedreichʼs ataxia (FA) is caused by a variant of the Frataxin ( FXN ) gene, leading to its downregulation and progressively impaired cardiac neurological function. Current gold-standard clinical scales use simplistic behavioral assessments, which require 18- 24-month-long trials determine if therapies are beneficial. Here we captured full-body movement kinematics from patients with wearable sensors, enabling us define digital features based on data nine FA (six females three males) age- sex-matched controls, who performed 8-m walk (8-MW) test 9-hole peg (9 HPT). We used machine learning combine these longitudinally predict scores patients, compared two standard Spinocerebellar Ataxia Functional Index (SCAFI) Scale for Assessment Rating (SARA). The enabled longitudinal predictions personal SARA SCAFI 9 months into future were 1.7 4 times more precise than using only scores, respectively. Unlike scales, accurately predicted gene expression levels each patient in cross-sectional manner. Our work demonstrates how data-derived biomarkers can track disease trajectories indicates potential such substantially reducing duration or size testing disease-modifying transcriptomics.

Language: Английский

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Omaveloxolone: a groundbreaking milestone as the first FDA-approved drug for Friedreich ataxia

Trends in Molecular Medicine, Journal Year: 2024, Volume and Issue: 30(2), P. 117 - 125

Published: Jan. 24, 2024

Language: Английский

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Role of iron in brain development, aging, and neurodegenerative diseases

Annals of Medicine, Journal Year: 2025, Volume and Issue: 57(1)

Published: March 4, 2025

It is now understood that iron crosses the blood-brain barrier via a complex metabolic regulatory network and participates in diverse critical biological processes within central nervous system, including oxygen transport, energy metabolism, synthesis catabolism of myelin neurotransmitters. During brain development, distributed throughout brain, playing pivotal role key such as neuronal myelination, neurotransmitter synthesis. In physiological aging, can selectively accumulate specific regions, impacting cognitive function leading to intracellular redox imbalance, mitochondrial dysfunction, lipid peroxidation, thereby accelerating aging associated pathologies. Furthermore, accumulation may be primary contributor neurodegenerative diseases Alzheimer's Parkinson's diseases. Comprehending diseases, utilizing iron-sensitive Magnetic Resonance Imaging (MRI) technology for timely detection or prediction abnormal neurological states, implementing appropriate interventions instrumental preserving normal system function.

Language: Английский

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Preexisting antibody assays for gene therapy: Considerations on patient selection cutoffs and companion diagnostic requirements

Molecular Therapy — Methods & Clinical Development, Journal Year: 2024, Volume and Issue: 32(1), P. 101217 - 101217

Published: Feb. 20, 2024

Recombinant adeno-associated virus (AAV) vectors are the leading delivery vehicle used for

Language: Английский

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Gene Therapy for Mitochondrial Diseases: Current Status and Future Perspective

Pharmaceutics, Journal Year: 2022, Volume and Issue: 14(6), P. 1287 - 1287

Published: June 17, 2022

Mitochondrial diseases (MDs) are a group of severe genetic disorders caused by mutations in the nuclear or mitochondrial genome encoding proteins involved oxidative phosphorylation (OXPHOS) system. MDs have wide range symptoms, ranging from organ-specific to multisystemic dysfunctions, with different clinical outcomes. The lack natural history information, limits currently available preclinical models, and phenotypic presentations seen MD patients all hampered development effective therapies. growing number pre-clinical trials over last decade has shown that gene therapy is viable precision medicine option for treating MD. However, several obstacles must be overcome, including vector design, targeted tissue tropism efficient delivery, transgene expression, immunotoxicity. This manuscript offers comprehensive overview state art MD, addressing main challenges, most feasible solutions, future perspectives field.

Language: Английский

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Recessive cerebellar and afferent ataxias — clinical challenges and future directions

Nature Reviews Neurology, Journal Year: 2022, Volume and Issue: 18(5), P. 257 - 272

Published: March 24, 2022

Language: Английский

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Large-scale expansions of Friedreich's ataxia GAA•TTC repeats in an experimental human system: role of DNA replication and prevention by LNA-DNA oligonucleotides and PNA oligomers

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 51(16), P. 8532 - 8549

Published: May 22, 2023

Friedreich's ataxia (FRDA) is caused by expansions of GAA•TTC repeats in the first intron human FXN gene that occur during both intergenerational transmissions and somatic cells. Here we describe an experimental system to analyze large-scale repeat cultured It employs a shuttle plasmid can replicate from SV40 origin cells or be stably maintained S. cerevisiae utilizing ARS4-CEN6. also contains selectable cassette allowing us detect accumulated upon transformation into yeast. We indeed observed massive repeats, making it genetically tractable study Further, stall replication fork progression, while frequency appears depend on proteins implicated stalling, reversal, restart. Locked nucleic acid (LNA)-DNA mixmer oligonucleotides peptide (PNA) oligomers, which interfere with triplex formation at vitro, prevented expansion these hypothesize, therefore, ultimately leading

Language: Английский

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AAV8 gene therapy reverses cardiac pathology and prevents early mortality in a mouse model of Friedreich’s ataxia

Molecular Therapy — Methods & Clinical Development, Journal Year: 2024, Volume and Issue: 32(1), P. 101193 - 101193

Published: Jan. 22, 2024

Friedreich's ataxia (FRDA) is an autosomal-recessive disorder primarily attributed to biallelic GAA repeat expansions that reduce expression of the mitochondrial protein frataxin (FXN). FRDA characterized by progressive neurodegeneration, with many patients developing cardiomyopathy progresses heart failure and death. The potential reverse or prevent progression cardiac phenotype was investigated in a mouse model FRDA, using adeno-associated viral vector (AAV8) containing coding sequence FXN gene. Fxnflox/null::MCK-Cre conditional knockout (FXN-MCK) has gene ablation prevents skeletal muscle, leading insufficiency, weight loss, morbidity. FXN-MCK mice received single intravenous injection AAV8 human (hFXN) (mFXN) genes under control phosphoglycerate kinase promoter. Compared vehicle-treated mice, AAV-treated displayed increases body weight, reversal deficits, survival without apparent toxicity liver for up 12 weeks postdose. tissue detected dose-dependent manner, exhibiting wide distribution throughout similar wild type, but more speckled. These results support AAV8-based approach treat FRDA-associated cardiomyopathy.

Language: Английский

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Recent Advances in the Elucidation of Frataxin Biochemical Function Open Novel Perspectives for the Treatment of Friedreich’s Ataxia

Frontiers in Neuroscience, Journal Year: 2022, Volume and Issue: 16

Published: March 2, 2022

Friedreich’s ataxia (FRDA) is the most prevalent autosomic recessive and associated with a severe cardiac hypertrophy less frequently diabetes. It caused by mutations in gene encoding frataxin (FXN), small mitochondrial protein. The primary consequence defective expression of FXN, basal protein levels decreased 70–98%, which foremost affects cerebellum, dorsal root ganglia, heart liver. FXN involved iron metabolism but its exact function has remained elusive highly debated since discovery. At cellular level, FRDA characterized general deficit biosynthesis iron-sulfur (Fe-S) clusters heme, accumulation deposition mitochondria, sensitivity to oxidative stress. Based on these phenotypes proposed ability bind iron, role as an storage providing for Fe-S cluster heme was initially proposed. However, this model challenged several other studies it now widely accepted that functions primarily biosynthesis, accumulation, deficiency stress appearing later secondary defects. Nonetheless, biochemical still debated. Several roles have been FXN: chaperone, gate-keeper detrimental sulfide production stimulator sulfur transfer accelerator. A picture emerging points toward unique accelerator key step between two components biosynthetic complex. These findings should foster development new strategies treatment FRDA. We will review here latest discoveries implication potential therapeutic

Language: Английский

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Liquid Chromatography–Mass Spectrometry Analysis of Frataxin Proteoforms in Whole Blood as Biomarkers of the Genetic Disease Friedreich’s Ataxia

Analytical Chemistry, Journal Year: 2023, Volume and Issue: 95(8), P. 4251 - 4260

Published: Feb. 17, 2023

Friedreich's ataxia (FRDA) is caused primarily by expanded GAA repeats in intron 1 of both alleles the FXN gene, which causes transcriptional silencing and reduced expression frataxin mRNA protein. FRDA characterized slowly progressive cardiomyopathy. Symptoms generally appear during adolescence, patients progress to wheelchair dependency usually late teens or early twenties with death on average 4th decade. There are two known mature proteoforms frataxin. Mitochondrial (frataxin-M) a 130-amino acid protein molecular weight 14,268 Da, there an alternatively spliced N-terminally acetylated 135-amino form (frataxin-E) 14,953 Da found erythrocytes. heart brain, but not secreted into systemic circulation, so it cannot be analyzed serum plasma. Blood readily accessible biofluid that contains numerous different cell types express We have pig blood can serve as excellent surrogate matrix validate assay for because lost immunoprecipitation step used isolate human Frataxin-M expressed cells contain mitochondria, whereas extra-mitochondrial frataxin-E This means analysis whole provides information concentration without having individual types. In current study, we observed distributions levels sample 25 healthy controls 50 were completely separated from each other, suggesting 100% specificity sensitivity distinguishing cases, very unusual finding biomarker assay. Additionally, significantly correlated repeat length age onset higher correlations than those mitochondrial frataxin-M. These findings auger well using measured validated stable isotope dilution ultrahigh-performance liquid chromatography-multiple reaction monitoring/mass spectrometry monitor therapeutic interventions natural history FRDA. Our study also illustrates utility disease discovery validation.

Language: Английский

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