The ying and yang of idebenone: Not too little, not too much – cell death in NQO1 deficient cells and the mouse retina

C. Varricchio, K. Beirne, C. Heard, B. Newland, M. Rozanowska, A. Brancale, M. Votruba, Free Radical Biology and Medicine, 2019, doi:10.1016/j.freeradbiomed.2019.11.030.

Beneficial effects of idebenone are dependent on the expression of NQO1 in cells. There appears to be a patient-specific response to idebenone with high variability in therapeutic outcomes. A recent study suggested that the cytosolic enzyme NAD(P)H: quinone acceptor oxidoreductase (NQO1) is the major enzyme involved in the activation of idebenone, and the beneficial effects of idebenone are dependent on the expression of NQO1. Here, we confirm the NQO1-dependent activity of idebenone, but we also show, for the first time, that the cytotoxicity of idebenone is linked to cellular expression of NQO1. Upon idebenone administration, cells deficient in NQO1 show a marked decrease in viability in comparison to NQO1 expressing cells, with idebenone causing ROS production and deleterious effects on ATP levels and cell viability. The specific dependence of idebenone activity on NQO1 may also explain the variation in patient outcomes in clinical trials.

Single Ascending Dose Study of CTI-1601 Versus Placebo in Subjects With Friedreich's Ataxia

ClinicalTrials.gov Identifier: NCT04176991. Chondrial Therapeutics, Inc., November 26, 2019

Phase 1, A Phase 1 Single Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneous CTI-1601 Versus Placebo in Subjects With Friedreich's Ataxia.
CTI-1601 is a recombinant fusion protein and is intended to deliver human frataxin, the protein deficient in Friedreich's ataxia

Mitochondrial dysfunction in neurons in Friedreich's ataxia

Anna Stepanova, Jordi Magrané, Molecular and Cellular Neuroscience, 2019, 103419, doi:10.1016/j.mcn.2019.103419.

Friedreich's ataxia is a multisystemic genetic disorder within the family of mitochondrial diseases that is characterized by reduced levels of the essential mitochondrial protein frataxin. Based on clinical evidence, the peripheral nervous system is affected early, neuronal dysfunction progresses towards the central nervous system, and other organs (such as heart and pancreas) are affected later. However, little attention has been given to the specific aspects of mitochondria function altered by frataxin depletion in the nervous system. For years, commonly accepted views on mitochondria dysfunction in Friedreich's ataxia stemmed from studies using non-neuronal systems and may not apply to neurons, which have their own bioenergetic needs and present a unique, extensive neurite network. Moreover, the basis of the selective neuronal vulnerability, which primarily affects large sensory neurons in the dorsal root ganglia, large principal neurons in the dentate nuclei of the cerebellum, and pyramidal neurons in the cerebral cortex, remains elusive. In order to identify potential misbeliefs in the field and highlight controversies, we reviewed current knowledge on frataxin expression in different tissues, discussed the molecular function of frataxin, and the consequences of its deficiency for mitochondria structural and functional properties, with a focus on the nervous system.

Mitochondria Regulation in Ferroptosis

Hai Wang, Can Liu, Yongxin Zhao, Ge Gao, European Journal of Cell Biology, 2019, doi:10.1016/j.ejcb.2019.151058.

Ferroptosis is recognized as a new form of regulated cell death which is initiated by severe lipid peroxidation relying on reactive oxygen species (ROS) generation and iron overload. Targeted induction of ferroptosis was also considered as a potential therapeutic strategy to some oxidative stress diseases, including neurodegenerative disorders, ischemia-reperfusion injury, traumatic spinal cord injury. However, the pertinence between mitochondria and ferroptosis is still in dispute. Here we systematic elucidate the morphological characteristics and metabolic regulation of mitochondria in the regulation of ferroptosis.

TAK-831 for Friedreich Ataxia. Withdrawn from the Union Register of orphan medicinal products in November 2019

20/11/2019. European Medicines Agency.
On 1 April 2019, orphan designation (EU/3/19/2148) was granted by the European Commission to Takeda Pharma A/S, Denmark, for 4-hydroxy-6-{2-[4-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one (also known as TAK-831) for the treatment of Friedreich’s ataxia.

Please note that this product was withdrawn from the Union Register of orphan medicinal products in November 2019 on request of the Sponsor.


Key facts
Active substance:  4-hydroxy-6-{2-[4-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one
Disease / condition: Treatment of Friedreich’s ataxia
Date of first decision:  01/04/2019
Outcome: Withdrawn
EU designation number: EU/3/19/2148

N-terminomics/TAILS profiling of macrophages after chemical inhibition of legumain

Bethany M AndersonLuiz G. N. de AlmeidaHenna SekhonDaniel YoungAntoine DufourLaura Edgington-Mitchell; Biochemistry 2019, XXXX, XXX, XXX-XXX, Publication Date: November 14, 2019 doi:10.1021/acs.biochem.9b00821

We confirmed that frataxin, a mitochondrial protein associated with the formation of iron-sulfur clusters, can be cleaved by legumain. This further asserts a potential contribution of legumain to mitochondrial function and iron metabolism.

Analysis of Friedreich's ataxia patient clinical data reveals importance of accurate GAA repeat determination in disease prognosis and gender differences in cardiac measures

Mohammadmersad Ghorbani, Françoise Pousset, Allan Tucker, Stephen Swift, Paola Giunti, Michael Parkinson, David Gilbert, XiaoHui Liu, Annette Payne, Informatics in Medicine Unlocked, 2019, doi:10.1016/j.imu.2019.100266.

This work uses computer aided classification techniques to identify which measures of the disease progression, including accurate determination of the shortest allele repeat length, are the most informative when trying to predict likely disease progression and prognosis. Further we investigate the possibility of a gender difference in the progression of the disease. Our results highlight the importance of accurate determination GAA repeat length in any clinical predictions showing that the number of repeats is the best prognostic tool in FRDA and is strongly linked to the age at onset disease. Further that there are possible gender dependent differences in cardiac measurements recorded from patients of similar age of onset and GAA repeat length.

Metformin-dependent Exacerbation of Pathologies in Friedreich’s Ataxia

Free Radical Biology and Medicine, Volume 145, Supplement 1, 2019, Page S81, doi:10.1016/j.freeradbiomed.2019.10.216.

One case report describes metformin treatment for diabetes in a FRDA patient, he developed severe ventricular arrhythmia and died of cardiac failure during a surgery. Future research of FRDA-relevant tissues will better inform on disease exacerbation.

Left ventricular structural and functional changes in Friedreich ataxia – Relationship with body size, sex, age and genetic severity

Peverill RE, Romanelli G, Donelan L, Hassam R, Corben LA, Delatycki MB (2019); PLoS ONE 14(11): e0225147. doi:10.1371/journal.pone.0225147

In FRDA, increases in RWT and age-normalized RWT are the most frequent LV structural abnormalities, sex and body size are important determinants of most other LV structural variables in both children and adults, and increased genetic severity is associated with a smaller left ventricle and increased LV wall thickness in adults, but not associated with LV size or wall thickness in children.

Minoryx Therapeutics receives Orphan Drug Designation from the European Commission for leriglitazone in the treatment of Friedreich’s Ataxia

Mataró, Barcelona, Spain and Charleroi, Belgium, November 12, 2019 – Minoryx Therapeutics, a company that specializes in the development of innovative treatments for orphan Central Nervous System (CNS) diseases, today announces that its lead drug candidate, leriglitazone (MIN-102), has been granted Orphan Drug Designation by the European Commission in the treatment of Friedreich’s Ataxia.

Leriglitazone (MIN-102) is a novel, brain penetrant, orally bioavailable and selective PPARγ agonist that engages the target receptor within the central nervous system. The disease-modifying potential and unique mode-of-action of leriglitazone have been demonstrated in multiple preclinical CNS disease models showing that it has an anti-oxidant, anti-inflammatory and neuroprotective effect. Leriglitazone improves mitochondrial function and biogenesis, promotes remyelination, ameliorates lipid metabolism and delays the progression of neurological disability. Leriglitazone is currently in late-stage clinical development in adrenomyeloneuropathy (AMN) and Friedreich’s Ataxia (FRDA).

“We are very pleased that, following the recent FDA Orphan Drug Designation for leriglitazone in Friedreich’s Ataxia, the European Commission has also granted Orphan Drug Status, further demonstrating the potential of this novel drug candidate and our commitment to changing the lives of patients suffering from severe orphan diseases,” said Marc Martinell, CEO of Minoryx. “Leriglitazone is our lead drug candidate currently in late-stage clinical development in a number of life-threatening orphan CNS diseases. Patient enrollment has been completed in both the AMN and the FRDA studies and we are on track to present our results by the end of 2020.”