New developments in pharmacotherapy for Friedreich ataxia

Clay, A; Hearle, Patrick; Schadt, Kim; Lynch, David R.

doi:10.1080/14656566.2019.1639671

Cited by 35 publications

(32 citation statements)

References 157 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Many of those compounds are already adopted in clinical trials, such as DMF that is used for the treatment of relapsing multiple sclerosis (Tecfidera, Biogen-Idec) [18,19,20], EPI-743 evaluated in mitochondrial diseases [25,27,28], idebenone, in treating Leber hereditary optic neuropathy (LHON) [29,30] and in FRDA [31,32], and NAC showing protective effects in frataxin-deficient cell types and in ethylmalonic encephalopathy [33,34].…”

Section: Introductionmentioning

confidence: 99%

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

Petrillo

D’Amico

Rosa

et al. 2019

IJMS

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

Petrillo

D’Amico

Rosa

et al. 2019

IJMS

View full text Add to dashboard Cite

show abstract

“…The complexity of FRDA and its pathophysiology may explain the failure of luvadaxistat to significantly improve FRDA symptomatology. 13 For example, the deficiency of FXN in FRDA affects multiple biochemical pathways. Consequently, pharmacological agents affecting downstream targets may be limited in their ability to improve symptomatology, particularly if they only act on a single neurotransmitter system, 13 i.e., a single neurological pathway is insufficient to demonstrate benefit to a wide range of patients with FRDA, particularly if those patients are in different stages of the disease.…”

Section: Discussionmentioning

confidence: 99%

Results of a randomized double‐blind study evaluating luvadaxistat in adults with Friedreich ataxia

Wang

Norton

et al. 2021

Ann Clin Transl Neurol

View full text Add to dashboard Cite

Objectives: Friedreich ataxia (FRDA) is a rare disorder with progressive neurodegeneration and cardiomyopathy. Luvadaxistat (also known as TAK-831; NBI-1065844), an inhibitor of the enzyme D-amino acid oxidase, has demonstrated beneficial effects in preclinical models relevant to FRDA. This phase 2, randomized, double-blind, placebo-controlled, parallel-arm study evaluated the efficacy and safety of oral luvadaxistat in adults with FRDA. Methods: Adult patients with FRDA were randomized 2:1:2 to placebo, luvadaxistat 75 mg twice daily (BID), or luvadaxistat 300 mg BID for 12 weeks. The primary endpoint changed from baseline at week 12 on the inverse of the time to complete the nine-hole peg test (9-HPT À1 ), a performance-based measure of the function of the upper extremities and manual dexterity. Comparisons between luvadaxistat and placebo were made using a mixed model for repeated measures. Results: Of 67 randomized patients, 63 (94%) completed the study. For the primary endpoint, there was no statistically significant difference in change from baseline on the 9-HPT À1 (seconds À1 ) at week 12 between placebo (0.00029) and luvadaxistat 75 mg BID (À0.00031) or luvadaxistat 300 mg BID (À0.00059); least squares mean differences versus placebo (standard error) were À0.00054 (0.000746) for the 75 mg dose and À0.00069 (0.000616) for the 300 mg dose. Luvadaxistat was safe and well tolerated; the majority of reported adverse events were mild in intensity. Interpretation: Luvadaxistat was safe and well tolerated in this cohort of adults with FRDA; however, it did not demonstrate efficacy as a treatment for this condition.

show abstract

“…FA is a neurodegenerative disorder for which no cure is actually at our disposal. Due to the ubiquitous nature of the frataxin expression, FA is a multisystemic disease where, despite the death of dorsal root ganglia (DRG) neurons and cardiomyopathy, which represent, respectively, the first pathologic event and the primary cause of death [21,146], patients also display a number of secondary defects including diabetes, hearing loss, visual impairments, and cognitive deficits [146]. As impairments in the main pathologic targets can be reflected in other cellular districts, even less affected (i.e., blood), this suggests that the identification of sensitive and reliable biomarkers in FA could be useful in evaluating both the effectiveness of specific therapies and in monitoring the disease progression.…”

Section: Discussionmentioning

confidence: 99%

“…Currently, there are no approved therapies for treating FA. Nevertheless, more than 20 molecules have been tested in clinics, leading in some cases to improvement in patients' living conditions and disease progression [146,147]. It is important to note that typical clinical trials in FA consist of small pilots, with some larger follow-up studies, which often do not reach 12 months in duration [148].…”

Section: Nrf2 Signaling Network As a Biomarker In The Evaluation Of Fmentioning

confidence: 99%

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

Rosa

Bertini

Piemonte

2020

IJMS

View full text Add to dashboard Cite

Friedreich’s ataxia (FA) is a trinucleotide repeats expansion neurodegenerative disorder, for which no cure or approved therapies are present. In most cases, GAA trinucleotide repetitions in the first intron of the FXN gene are the genetic trigger of FA, determining a strong reduction of frataxin, a mitochondrial protein involved in iron homeostasis. Frataxin depletion impairs iron–sulfur cluster biosynthesis and determines iron accumulation in the mitochondria. Mounting evidence suggests that these defects increase oxidative stress susceptibility and reactive oxygen species production in FA, where the pathologic picture is worsened by a defective regulation of the expression and signaling pathway modulation of the transcription factor NF-E2 p45-related factor 2 (NRF2), one of the fundamental mediators of the cellular antioxidant response. NRF2 protein downregulation and impairment of its nuclear translocation can compromise the adequate cellular response to the frataxin depletion-dependent redox imbalance. As NRF2 stability, expression, and activation can be modulated by diverse natural and synthetic compounds, efforts have been made in recent years to understand if regulating NRF2 signaling might ameliorate the pathologic defects in FA. Here we provide an analysis of the pharmaceutical interventions aimed at restoring the NRF2 signaling network in FA, elucidating specific biomarkers useful for monitoring therapeutic effectiveness, and developing new therapeutic tools.

show abstract

New developments in pharmacotherapy for Friedreich ataxia

Cited by 35 publications

References 157 publications

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

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

Results of a randomized double‐blind study evaluating luvadaxistat in adults with Friedreich ataxia

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

Contact Info

Product

Resources

About