Omaveloxolone: an activator of Nrf2 for the treatment of Friedreich ataxia

Profeta, Victoria; McIntyre, Kellie; Wells, McKenzie; Park, Courtney; Lynch, David R.

doi:10.1080/13543784.2023.2173063

Cited by 21 publications

(7 citation statements)

References 90 publications

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“…Recent studies demonstrated the efficacy of Nrf2-activating drugs in cellular and animal model of FRDA [ 16 , 27 , 74 ]. More importantly, on February 2023 the U.S. Food and Drug Administration has approved the Nrf2 activator Omaveloxolone [ 75 ] as the first therapy indicated to treat FRDA patients aged 16 years and over [ 76 ]. Besides the multiple antioxidant effects, some Nrf2 inducers also increase the transcription of FXN gene in FRDA cells.…”

Section: Discussionmentioning

confidence: 99%

Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia Cells

Luffarelli

Panarello

Quatrana

et al. 2023

IJMS

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Friedreich’s ataxia (FRDA) is a rare monogenic disease characterized by multisystem, slowly progressive degeneration. Because of the genetic defect in a non-coding region of FXN gene, FRDA cells exhibit severe deficit of frataxin protein levels. Hence, 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.

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Section: Discussionmentioning

confidence: 99%

Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia Cells

Luffarelli

Panarello

Quatrana

et al. 2023

IJMS

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“…As a disorder affecting mitochondrial oxidative phosphorylation capacity and other metabolic processes in multiple organ systems, numerous therapeutic approaches that impact metabolism are under investigation for this disease. Omaveloxolone, a nuclear factor erythroid 2‐related factor (Nrf2) activator, was recently approved for the treatment of FRDA on the basis of its ability to slow disease progression 6 . Identification and validation of outcome measures with which to assess the effectiveness of interventions in FRDA, in particular for its cardiac manifestations, remain important research priorities.…”

Section: Introductionmentioning

confidence: 99%

“…Omaveloxolone, a nuclear factor erythroid 2-related factor (Nrf2) activator, was recently approved for the treatment of FRDA on the basis of its ability to slow disease progression. 6 Identification and validation of outcome measures with which to assess the effectiveness of interventions in FRDA, in particular for its cardiac manifestations, remain important research priorities.…”

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confidence: 99%

Cardiopulmonary exercise testing on adaptive equipment in children and adults with Friedreich ataxia

Cilenti,

Tamaroff,

Capiola

et al. 2024

Muscle and Nerve

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Introduction/AimsTraditional exercise is often difficult for individuals with Friedreich ataxia (FRDA), and evidence is limited regarding how to measure exercise performance in this population. We evaluated the feasibility, reliability, and natural history of adaptive cardiopulmonary exercise test (CPET) performance in children and adults with FRDA.MethodsParticipants underwent CPET on either an arm cycle ergometer (ACE) or recumbent leg cycle ergometer (RLCE) at up to four visits (baseline, 2 weeks, 4 weeks, and 1 year). Maximum work, oxygen consumption (peak VO2), oxygen (O2) pulse, and anaerobic threshold (AT) were measured in those who reached maximal volition. Test–retest reliability was assessed with intraclass coefficients, and longitudinal change was assessed using regression analysis.ResultsIn our cohort (N = 23), median age was 18 years (interquartile range [IQR], 14–23), median age of FRDA onset was 8 years (IQR 6–13), median Friedreich Ataxia Rating Scale score was 58 (IQR 54–62), and GAA repeat length on the shorter FXN allele (GAA1) was 766 (IQR, 650–900). Twenty‐one (91%) completed a maximal CPET (n = 8, ACE and n = 13, RLCE). Age, sex, and GAA1 repeat length were each associated with peak VO2. Preliminary estimates demonstrated reasonable agreement between visits 2 and 3 for peak work by both ACE and RLCE, and for peak VO2, O2 pulse, and AT by RLCE. We did not detect significant performance changes over 1 year.DiscussionAdaptive CPET is feasible in FRDA, a relevant clinical trial outcome for interventions that impact exercise performance and will increase access to participation as well as generalizability of findings.

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“…Omaveloxolone activates nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor suppressed in FRDA, and that is responsible for maintaining redox homeostasis and counteracting the production of reactive oxygen species. Nrf2 activation through Omaveloxolone has shown to improve mitochondrial function and relief of some symptoms 34 . Additional disease-modifying trials are ongoing and comprise a variety of substances targeting pathways underlying FRDA pathogenesis 11 .…”

Section: Introductionmentioning

confidence: 99%

Anti-gene oligonucleotides targeting Friedreich’s ataxia expanded GAA•TTC repeats increase Frataxin expression

Mozafari,

Milagres,

Rocha

et al. 2024

Preprint

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Friedreichs ataxia (FRDA) is a progressive, autosomal recessive ataxia caused, in the majority of cases, by homozygous expansion of GAA:TTC triplet-repeats in the first intron of the frataxin (FXN) gene. GAA:TTC repeat expansion results in the formation of non-B DNA intramolecular triplex structure (H-DNA) as well as changes in the epigenetic landscape at FXN loci and heterochromatin formation. Expansion of intronic GAA:TTC repeats is associated with reduced levels of FXN mRNA and protein resulting in disease development. Previously, we reported that DNA-binding anti-gene oligonucleotides (AGOs) targeting the GAA:TTC repeat expansion abolished H-DNA formation. Here, we demonstrate that targeting repeat-expanded chromosomal DNA using single-strand locked nucleic acid (LNA)-DNA mixmer AGOs increases FXN mRNA and protein expression in patient-derived cells. We examined numerous LNA-DNA AGOs and found that the design, length and their LNA composition have a high impact on the effectiveness of the treatment. Collectively, our results demonstrate the unique capability of specifically designed ONs targeting the GAA:TTC DNA repeats to upregulate FXN gene expression.

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Omaveloxolone: an activator of Nrf2 for the treatment of Friedreich ataxia

Cited by 21 publications

References 90 publications

Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia Cells

Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia Cells

Cardiopulmonary exercise testing on adaptive equipment in children and adults with Friedreich ataxia

Anti-gene oligonucleotides targeting Friedreich’s ataxia expanded GAA•TTC repeats increase Frataxin expression

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