Targeting NRF2 for the Treatment of Friedreich’s Ataxia: A Comparison among Drugs

Abstract

NRF2 (Nuclear factor Erythroid 2-related Factor 2) signaling is impaired in Friedreich’s Ataxia (FRDA), an autosomal recessive disease characterized by progressive nervous system damage and degeneration of nerve fibers in the spinal cord and peripheral nerves. The loss of frataxin in patients results in iron sulfur cluster deficiency and iron accumulation in the mitochondria, making FRDA a fatal and debilitating condition. There are no currently approved therapies for the treatment of FRDA and molecules able to activate NRF2 have the potential to induce clinical benefits in patients. In this study, we compared the efficacy of six redox-active drugs, some already adopted in clinical trials, targeting NRF2 activation and frataxin expression in fibroblasts obtained from skin biopsies of FRDA patients. All of these drugs consistently increased NRF2 expression, but differential profiles of NRF2 downstream genes were activated. The Sulforaphane and N-acetylcysteine were particularly effective on genes involved in preventing inflammation and maintaining glutathione homeostasis, the dimethyl fumarate, omaxevolone, and EPI-743 in counteracting toxic products accumulation, the idebenone in mitochondrial protection. This study may contribute to develop synergic therapies, based on a combination of treatment molecules.

Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue

“…Interestingly, NRF2, besides being an up-stream modulator of the expression of antioxidant genes and protection against oxidative stress/ferroptosis 56,57 , positively regulates enzymes involved in mitochondrial oxidation of FAs 29 and adipogenesis 58,59 . Based on this, NRF2 inducers, already proposed as FRDA therapeutics 53,54,60 could be also advantageous for preserving BAT integrity and mitigating metabolic disturbances of FRDA patients via a BAT-dependent manner. Accordingly, NRF2 targeting has been proposed as promising for treating T2D 61 .…”

Disarrangement of Endoplasmic reticulum-mitochondria communication impairs Ca2+homeostasis in FRDA

“…There are several lines of evidence highlighting the key role of antioxidants in FRDA (Ulatowski & Manor, 2015). In 2008, Cooper et al found promising improvements with a combined Coenzyme Q10-Vitamin E therapy in FRDA patients (Cooper et al, 2008) and NAC, a direct donor of cysteines, has recently been used as a Nuclear factor E2-related factor 2 (Nrf2) modulator in FRDA fibroblasts, exhibiting neuroprotective features and increasing frataxin expression (Petrillo et al, 2019). We have recovered function and structure of MAMs with NAC or Trolox treatment, demonstrating a direct relationship between Ca 2+ dyshomeostasis and oxidative stress.…”

The NRF2 Signaling Network Defines Clinical Biomarkers and Therapeutic Opportunity in Friedreich’s Ataxia

“…In line with this principle, as has been observed in other neurodegenerative diseases where oxidative stress is increased [76], in FA the frataxin deficiency-induced oxidative stress should stabilize NRF2 and induce an up-regulation of ARE-dependent gene transcription. Nevertheless, NRF2 signaling is impaired in several FA cells and animal models [10,36,[56][57][58][59]77]. The mechanisms underlying NRF2 deficiency in FA are still poorly understood, although, starting from the first decade of the 2000s some studies reported a reduced antioxidant defense as a consequence of frataxin depletion [78], while the over-expression of frataxinwas able to potentiate the antioxidant responses [79].…”

“…The SFN-mediated NRF2 induction, through the interaction with the Cys 151 of KEAP1, has beneficial effects in pre-clinical models and in the clinical treatment of neurological conditions [90,91]. In FA, in vitro SFN treatment partially rescues the cellular phenotypic defects in frataxin-silenced motor neuron-like cells [92], in neural stem cells isolated from the KIKO FA mouse model [10] and in FA fibroblasts [77]. Despite this, SFN is actually not adopted in FA clinical trials, probably because of its off-target activity [93] and the low blood-brain barrier permeability [94].…”

“…Although a direct interaction of quinone compounds with KEAP1 Cys residues has not yet been described, indirect proof has led to the proposal that these molecules are NRF2 inducers. In addition to their antioxidant activity: (i) coenzyme Q 10 , vitamin E, idebenone, EPI-743, and MitoQ are able to increase NRF2 stability/expression and to induce NQO1 activity in cells and in animal models [77,[102][103][104][105][106], which is a renowned method to evaluate the functionality of NRF2 inducers [107]; (ii) the chemical characteristics of the para-benzoquinone moiety make these molecules able to react with thiol compounds [108] and with protein-contained cysteine residues [109]; (iii) in silico modeling analyses showed a potential interaction between the vitamin E and KEAP1 [110], suggesting a common behavior for molecules sharing the same biochemical structure; and (iv) in particular conditions, especially in an oxidative stress-induced environment [111][112][113][114], these compounds can act as pro-oxidants thus directly inducing NRF2 activity (i.e., by interacting with KEAP1) or increasing the amount of oxidative species in the cell.…”