A Study to Assess the Efficacy and Safety of Vatiquinone for the Treatment of Participants With Friedreich Ataxia

ClinicalTrials.gov Identifier: NCT04577352

Randomized, Parallel-Arm, Double-Blind, Placebo-Controlled Study With Open-Label Extension to Assess the Efficacy and Safety of Vatiquinone for the Treatment of Friedreich Ataxia (MOVE-FA).

Lead Sponsor: PTC Therapeutics. Start Date November 17, 2020, Phase 2/Phase 3, Location Countries: Australia, Canada, Italy, United States. The primary objective of the study is to evaluate the efficacy (using the modified Friedreich Ataxia Rating Scale [mFARS]) and safety of vatiquinone in participants with Friedreich ataxia (FA).

Neurodegenerative Diseases and the Auditory-Vestibular System

Mehta, Zarin PhD; Hale, Troy AuD; McMillan, Raechal BS; Sudaj, Gabriel BS; Pullman, Kelly AuD; Belus, Gail AuD; The Hearing Journal: October 2020 - Volume 73 - Issue 10 - p 38,40,41 doi: 10.1097/01.HJ.0000719804.32573.ea

Physicians and audiologists should consider auditory-vestibular dysfunction in patients with neurodegenerative diseases even when peripheral hearing sensitivity is normal.

Recapitulating the frataxin activation mechanism in an engineered bacterial cysteine desulfurase supports the architectural switch model

Shachin Patra, Cheng-Wei Lin, Manas K. Ghosh, Steven M. Havens, Seth A. Cory, David H. Russell, David P. Barondeau bioRxiv 2020.10.06.326603; doi:10.1101/2020.10.06.326603

Overall, these studies indicate a weakening of the homodimeric interface was a key development during the evolution of the eukaryotic system and provide new insights into the role of FXN.

Expanding the genotype–phenotype correlation of childhood sensory polyneuropathy of genetic origin

Samya Chakravorty, Rachel Logan, Molly J. Elson, Rebecca R. Luke & Sumit Verma; Sci Rep 10, 16184 (2020). doi:10.1038/s41598-020-73219-5 

Our single-center study shows genetic sensory polyneuropathies associated with progressive neurodegenerative disorders such as mitochondrial ataxia, Friedreich ataxia, spinocerebellar ataxia type 2, ataxia telangiectasia, spastic paraplegia, giant axonal neuropathy, and fumarate hydratase deficiency.

Emerging therapies in Friedreich's Ataxia

Zesiewicz TA, Hancock J, Ghanekar SD, Kuo SH, Dohse CA, Vega J. ; Expert Rev Neurother. 2020 Sep 21:1-14. doi:10.1080/14737175.2020.1821654. 

Areas covered include past and emerging therapies for FRDA, including antioxidants and mitochondrial-related agents, nuclear factor erythroid-derived 2-related factor 2 (Nrf2) activators, deuterated polyunsaturated fatty acids, iron chelators, histone deacetylase (HDAC) inhibitors, trans-activator of transcription (TAT)-frataxin, interferon gamma (IFNγ), erythropoietin, resveratrol, gene therapy, and anti-sense oligonucleotides (ASOs), among others.

Mechanism of Iron–Sulfur Cluster Assembly: In the Intimacy of Iron and Sulfur Encounter

Srour, B.; Gervason, S.; Monfort, B.; D’Autréaux, B. . Inorganics 2020, 8, 55.   doi:10.3390/inorganics8100055

In this paper, we review the most recent advances on the mechanism of assembly for the founding member of the Fe–S cluster family, the [2Fe2S] cluster that is the building block of all other Fe–S clusters. The aim is to provide a survey of the mechanisms of iron and sulfur insertion in the scaffold proteins by examining how these processes are coordinated, how sulfide is produced and how the dinuclear [2Fe2S] cluster is formed, keeping in mind the question of the physiological relevance of the reconstituted systems. We also cover the latest outcomes on the functional role of the controversial frataxin protein in Fe–S cluster biosynthesis.

Oxidative stress-dependent frataxin inhibition mediated alcoholic hepatocytotoxicity through ferroptosis

Jingjing Liu, Hui He, Jing Wang, Xiaoping Guo, Hongkun Lin, Huimin Chen, Chunjie Jiang, Li Chen, Ping Yao, Yuhan Tang, Toxicology, 2020, 152584, doi:10.1016/j.tox.2020.152584. Frataxin deficiency enhanced ferroptosis driven by ethanol via evaluating the levels of lactate dehydrogenase, cell morphological changes, mitochondrial labile iron pool, and lipid peroxidation. Conversely, restoring frataxin alleviated the sensitivity to ferroptosis. In addition, frataxin overexpression mitigated the sensitivity of ethanol-induced ferroptosis in HepG2CYP2E1+/+.

Home Based Tele-exercise for People With Chronic Neurological Impairments: COVID and Beyond (Telex)

ClinicalTrials.gov Identifier: NCT04564495. To assess the impact of a 12-week virtual seated physical intervention on cardiovascular health and wellness in people with chronic neurological impairments (CNI). Locations: United States, New York, Burke Neurological Institute, September 25, 2020

Extra-mitochondrial mouse frataxin and its implications for mouse models of Friedreich’s ataxia

Liwei Weng, Laurent Laboureur, Qingqing Wang, Lili Guo, Peining Xu, Leah Gottlieb, David R. Lynch, Clementina Mesaros & Ian A. Blair; Sci Rep 10, 15788 (2020). doi:10.1038/s41598-020-72884-w 

Mature mouse frataxin (78-207) only contributes 7–15% to the total frataxin protein present in mouse tissues. We have also found that truncated mature frataxin (79-207) is present primarily in the cytosol of mouse liver; whereas, frataxin (78-207) is primarily present in the mitochondria. These findings, which provide support for the role of extra-mitochondrial frataxin in the etiology of Friedreich’s ataxia, also have important implications for studies of mitochondrial dysfunction conducted in mouse models of frataxin deficiency.

Apart from our own studies on frataxin isoform E, several other studies have suggested that human mature frataxin can have an extra-mitochondria location. Alternatively, processing of the mature mouse frataxin could proceed in a different manner than in humans. If this is the case, we would suggest that mouse models do not serve as a good model for humans. Finally, as human gene therapy is tested in mouse models, it is possible that the mature human protein will undergo truncations in the mouse tissues, although they will most likely be at different sites because of the differences in amino acid sequence at the amino-terminus compared to mouse frataxin. This will impact on the assessment of efficacy and safety of the human transgene constructs (such as CAG-hFXN-HA) in mouse models.

IXICO joins neuroimaging consortium focused on Friedreich’s Ataxia

24 Sep 2020. IXICO PLC (LON:IXI) said it has entered a five year collaboration with the Friedreich's Ataxia Research Alliance (FARA) to become a member of the TRACK-FA neuroimaging consortium, focused on exploring novel imaging markers for Friedreich’s Ataxia (FA). The company added that it will be an industry member and stakeholder in the consortium and will work alongside academic partners with expertise in neuroimaging and conducting clinical research in FA including Monash University in Australia), the University of Minnesota and Aachen University in Germany.