Inducible and reversible phenotypes in a novel mouse model of Friedreich’s Ataxia

Chandran, Vijayendran; Gao, Kun; Swarup, Vivek; Versano, Revital; Dong, Hongmei; Jordan, Maria C.; Geschwind, Daniel H.

doi:10.1101/137265

Cited by 18 publications

(43 citation statements)

References 114 publications

(127 reference statements)

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“…According to this hypothesis, "young" and immature iPSC-derived neurons could provide information on early disease mechanisms. Our FRDA CNS neurons do not show any phenotypical deficit like the ones described for other FRDA cell types or animal models (27,50,51,53,(69)(70)(71)(72)(73)(74)(75)(76)(77)(78). Complex I, Complex III and aconitase activity were all similar to unaffected neurons and so were oxygen consumption, spare respiratory capacity, ATP production, reactive oxygen species formation and mitochondrial membrane potential (MMP, data not shown), while others have shown reduction in MMP (79), increased oxidative stress and decreased levels of Fe-S cluster-and lipoic acid-containing proteins (80) in iPSC-derived FRDA neurons compared to controls.…”

Section: Discussionsupporting

confidence: 67%

“…1D). Upregulation of synapsis related genes were also reported in the FRDAkd mouse (27). Axonogenesis was the most enriched term for upregulated genes shared between CNS and sensory neurons.…”

Section: Discussionmentioning

confidence: 76%

“…These changes are small but involve multiple aspects of cell metabolism. FRDA neurons show a decrease in mitochondrial protein transcript levels, such as components of the ATP synthase complex and of complex I (black module), all of which have been described in FRDA (23,27,(49)(50)(51). We observe consistent changes in ECM organization, focal adhesion and related signaling (brown and magenta modules and SNs), possibly linked to cytoskeletal abnormalities that have been reported in FRDA cells (52)(53)(54).…”

Section: A Gene Expression Signature Of Frdamentioning

confidence: 93%

“…Additionally, similar to other neurodegenerative diseases, only certain cell types and tissues are affected, despite frataxin being ubiquitously expressed. Previous gene expression profiling studies aimed at addressing the molecular basis of FRDA pathophysiology have been conducted in mouse models that do not to fully recapitulate the human disease (18,(23)(24)(25)(26)(27) or human cells that do not represent an affected tissue (28)(29)(30)(31)(32)(33)(34). The advent of induced pluripotent stem cell (iPSC) technology (35) has allowed in vitro modeling of diseases that involve inaccessible human tissue (36).…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional profiling of isogenic Friedreich ataxia induced pluripotent stem cell-derived neurons

Lai¹,

Nachun²,

Petrosyan³

et al. 2018

Preprint

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Friedreich ataxia (FRDA) is a rare childhood neurodegenerative disorder with no effective treatment. FRDA is caused by transcriptional silencing of the FXN gene and consequent loss of the essential mitochondrial protein frataxin. Based on the knowledge that a GAA•TTC repeat expansion in the first intron of FXN leads to heterochromatin formation and gene silencing, we have shown that members of the 2-aminobenzamide family of histone deacetylase inhibitors (HDACi) reproducibly increase FXN mRNA levels in induced pluripotent stem cell (iPSC)derived FRDA neuronal cells and in peripheral blood mononuclear cells from patients treated with the drug in a phase I clinical trial. How the reduced expression of frataxin leads to neurological and other systemic symptoms in FRDA patients remains unclear. Similarly to other triplet repeat disorders, it is not known why only specific cells types are affected in the disease, primarily the large sensory neurons of the dorsal root ganglia and cardiomyocytes. The combination of iPSC technology and genome editing techniques offers the unique possibility of addressing these questions in a relevant cell model of the disease, without the confounding effect of different genetic backgrounds. We derived a set of isogenic iPSC lines that differ only in the length of the GAA•TTC repeats, using "scarless" gene-editing methods (helper-dependent adenovirus-mediated homologous recombination). To uncover the gene expression signature due to GAA•TTC repeat expansion in FRDA neuronal cells and the effect of HDACi on these changes, we performed transcriptomic analysis of iPSC-derived central nervous system (CNS)and isogenic sensory neurons by RNA sequencing. We find that multiple cellular pathways are commonly affected by the loss of frataxin in CNS and peripheral nervous system neurons and these changes are partially restored by HDACi treatment.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 76%

Section: A Gene Expression Signature Of Frdamentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Transcriptional profiling of isogenic Friedreich ataxia induced pluripotent stem cell-derived neurons

Lai¹,

Nachun²,

Petrosyan³

et al. 2018

Preprint

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“…Fe-S are prosthetic groups crucial for many biological functions, including the mitochondrial respiratory chain and iron metabolism 6 . Frataxin deficiency leads to dysregulation of Fe-S biogenesis, impairment of Fe-S enzymes, mitochondrial dysfunction, iron metabolism dysregulation and eventually to cellular dysfunction and death 7,8 .…”

Section: Introductionmentioning

confidence: 99%

High levels of frataxin overexpression leads to mitochondrial and cardiac toxicity in mouse models

Belbellaa

Reutenauer

Messaddeq

et al. 2020

Preprint

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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. 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 administrated, the resulting FXN protein level could reach very high levels in the heart, cerebellum, or in 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 mitochondria respiratory chain, ultrastructure and homeostasis, which lead to myofilaments alteration, cell death and fibrosis. Overall, this study underlines the need, during the development of gene therapy approaches, to consider appropriately vector potency, long term safety and biomarkers to monitor such events.

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Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study)

Lynch

Chin

Delatycki

et al. 2020

Annals of Neurology

168

136

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Objective Friedreich ataxia (FA) is a progressive genetic neurodegenerative disorder with no approved treatment. Omaveloxolone, an Nrf2 activator, improves mitochondrial function, restores redox balance, and reduces inflammation in models of FA. We investigated the safety and efficacy of omaveloxolone in patients with FA. Methods We conducted an international, double‐blind, randomized, placebo‐controlled, parallel‐group, registrational phase 2 trial at 11 institutions in the United States, Europe, and Australia (NCT02255435, EudraCT2015‐002762‐23). Eligible patients, 16 to 40 years of age with genetically confirmed FA and baseline modified Friedreich's Ataxia Rating Scale (mFARS) scores between 20 and 80, were randomized 1:1 to placebo or 150mg per day of omaveloxolone. The primary outcome was change from baseline in the mFARS score in those treated with omaveloxolone compared with those on placebo at 48 weeks. Results One hundred fifty‐five patients were screened, and 103 were randomly assigned to receive omaveloxolone (n = 51) or placebo (n = 52), with 40 omaveloxolone patients and 42 placebo patients analyzed in the full analysis set. Changes from baseline in mFARS scores in omaveloxolone (−1.55 ± 0.69) and placebo (0.85 ± 0.64) patients showed a difference between treatment groups of –2.40 ± 0.96 ( p = 0.014). Transient reversible increases in aminotransferase levels were observed with omaveloxolone without increases in total bilirubin or other signs of liver injury. Headache, nausea, and fatigue were also more common among patients receiving omaveloxolone. Interpretation In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It represents a potential therapeutic agent in FA. ANN NEUROL 2021;89:212–225

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Inducible and reversible phenotypes in a novel mouse model of Friedreich’s Ataxia

Abstract: 11Friedreich's ataxia (FRDA), the most common inherited ataxia, is caused by recessive mutations that

Cited by 18 publications

References 114 publications

Transcriptional profiling of isogenic Friedreich ataxia induced pluripotent stem cell-derived neurons

Transcriptional profiling of isogenic Friedreich ataxia induced pluripotent stem cell-derived neurons

High levels of frataxin overexpression leads to mitochondrial and cardiac toxicity in mouse models

Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study)

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