ArticleMolecular therapy. Methods & clinical development2020
High Levels of Frataxin Overexpression Lead to Mitochondrial and Cardiac Toxicity in Mouse Models.
Article in Molecular therapy. Methods & clinical development, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
53 citing papers in PubMed, 67 citations in OpenAlex.
- Edited HSPCs rescue frataxin deficiency and inflammation-driven multisystemic pathology in Friedreich's ataxia mice.The Journal of clinical investigation · 2026Article
- Therapeutic upregulation of gene expression in inherited cardiomyopathies from current approaches to future directions.Nature cardiovascular research · 2026Review
- Mitochondrial Quality Control in Inherited Mitochondrial Cardiomyopathy: Convergent Pathobiology and a Testable Therapeutic Framework.International journal of molecular sciences · 2026Review
- The RNA structural code: orchestrating gene expression and enabling precision therapies.Acta pharmacologica Sinica · 2026Review
- Adeno-Associated virus-based approaches for mitochondrial diseases: advances and challenges.Molecular psychiatry · 2026Review
- Advances in Gene and Cellular Therapy in Friedreich Ataxia.Molecular diagnosis & therapy · 2026Review
- Challenging the more-is-better dogma: A precision-optimized AAV gene therapy for SMA.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Therapeutic activity of a hematopoietic stem cell-delivered cell-penetrating frataxin in Friedreich's ataxia models.Cell reports. Medicine · 2026Article
- Development of a secretable frataxin for enhanced efficacy in treating Friedreich's Ataxia.Molecular therapy. Advances · 2026Article
- Development of an AAV-based gene therapy for the ocular phenotype of Friedreich's ataxia.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Article
- Article
- Recent developments in Friedreich's ataxia: a state-of-the-art review.Brain communications · 2026Review
- Tunable, proteolytic dosage control of CRISPR-Cas systems enables precise gene therapy for dosage sensitive disorders.bioRxiv : the preprint server for biology · 2025Article
- Autosomal Recessive Cerebellar Ataxias: Translating Genes to Therapies.Annals of neurology · 2025Review
- Pharmacokinetics and Pharmacodynamics of Nomlabofusp in Non-clinical Studies of Friedreich's Ataxia.The AAPS journal · 2025Article
- Model-guided design of microRNA-based gene circuits supports precise dosage of transgenic cargoes into diverse primary cells.Cell systems · 2025Article
- Current clinical applications of AAV-mediated gene therapy.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Large-scale discovery of potent, compact and erythroid specific enhancers for gene therapy vectors.Nature communications · 2025Article
- A global perspective on research advances and future challenges in Friedreich ataxia.Nature reviews. Neurology · 2025Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Friedreich ataxia (FA) is currently an incurable inherited mitochondrial disease caused by reduced levels of frataxin (FXN). Cardiac dysfunction is the main cause of premature death in FA. Adeno-associated virus (AAV)-mediated gene therapy constitutes a promising approach for FA, as demonstrated in cardiac and neurological mouse models. While the minimal therapeutic level of FXN protein to be restored and biodistribution have recently been defined for the heart, it is unclear if FXN overexpression could be harmful. Indeed, depending on the vector delivery route and dose administered, the resulting FXN protein level could reach very high levels in the heart, cerebellum, or off-target organs such as the liver. The present study demonstrates safety of FXN cardiac overexpression up to 9-fold the normal endogenous level but significant toxicity to the mitochondria and heart above 20-fold. We show gradual severity with increasing FXN overexpression, ranging from subclinical cardiotoxicity to left ventricle dysfunction. This appears to be driven by impairment of the mitochondria respiratory chain and ultrastructure, which leads to cardiomyocyte subcellular disorganization, cell death, and fibrosis. Overall, this study underlines the need, during the development of gene therapy approaches, to consider appropriate vector expression level, long-term safety, and biomarkers to monitor such events.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.