A Study to Assess the Efficacy and Safety of Vatiquinone for the Treatment of Participants With Friedreich Ataxia (MOVE-FA)

ClinicalTrials.gov Identifier: NCT04577352; December 19, 2020 

Sponsors and Collaborators PTC Therapeutics 

Double-blind, placebo-controlled phase, participants will be stratified by baseline mFARS score (<40 age="" and="" at="" disease="" of="" onset="" or="" screening="" versus="" years="">21 years) and randomized to receive either vatiquinone or placebo using interactive web response system (IWRS). Following completion of the randomized, double-blind, placebo-controlled phase (72 weeks), participants will enter into an open-label extension phase (24 weeks) during which they will receive open-label treatment with vatiquinone at the dose they received in the randomized phase of the study (for participants entering the extension phase who initially received placebo, the dose of vatiquinone will be determined based on age and weight) and then a safety follow-up (10-30 days after last dose).

Insights Into the Roles of the Sideroflexins / SLC56 Family in Iron Homeostasis and Iron-Sulfur Biogenesis

Tifoun, N.; De las Heras, J.M.; Guillaume, A.; Bouleau, S.; Mignotte, B.; Le Floch, N.; Preprints 2020, 2020120583 doi: 10.20944/preprints202012.0583.v1. 

Frataxin (FXN) is a mitochondrial chaperone that interacts with aconitase in a citrate389 dependent manner to convert (3Fe-4S)1+ inactive enzyme into [4Fe-4S]2+ active one within the Krebs cycle. It also interacts with the ISCU-NFS1 (Iron-Sulfur Cluster Scaffold-Cysteine desulfurase) in the final steps of Fe-S formation [81,82]. The reduction of mitochondrial aconitase (ACO2) in SFXN4 KO cells suggests that SFXN4 could participate in the Fe-S biosynthesis maybe through an interaction with Frataxin (FXN). IIt has been previously reported that FECH, an important enzyme for heme biosynthesis, Mfrn1, an iron transporter into the mitochondria, and ABCB10, a protoporphyrin IX transporter, could form a complex in mouse erythroleukemia (MEL) cells to direct iron incorporation into protoporphyrin to form heme . Taken together, those results open the possibility that SFXN4 and FXN interact with other proteins such as aconitase or the ISCU-NFS1 multimeric complex to maturate the Fe-S clusters. We have recently performed a screen with the aim to identify the direct partners of SFXN1 protein in MCF7 cells (Tifoun et al., in preparation) and, even though Sfxn1 does not interact directly with FXN, it is still possible that Sfxn4 could do so. In Sfxn4 mutants Fe-S synthesis is reduced, pointing out that Sfxn4 may play a role in the first steps of Fe-S cluster formation, maybe through FXN interaction. A recent study shows that the ISC (Iron Sulfur Cluster, composed by NFS1, ISCU and FXN) function requires L-Cysteine to generate de disulfide groups necessary to form the Fe-S clusters.

Seelos Therapeutics Announces Issuance of a Patent for Trehalose (SLS-005) in Israel

NEW YORK, Dec. 21, 2020 /PRNewswire/ -- Seelos Therapeutics, Inc. (Nasdaq: SEEL), a clinical-stage biopharmaceutical company focused on the development of therapies for central nervous system disorders and rare diseases, announced today that it has been issued Israeli patent number 241757 by the State of Israel Patent Office titled: "TREATMENT OF PROTEIN AGGREGATION MYOPATHIC AND NEURODEGENERATIVE DISEASES BY PARENTERAL ADMINISTRATION OF TREHALOSE".

 The issued patent covers a method of using trehalose (SLS-005) to treat several neurodegenerative conditions including amyotrophic lateral sclerosis (ALS), Sanfilippo syndrome, oculopharyngeal muscular dystrophy (OPMD), Huntington's disease, spinocerebellar ataxia (SCA), spinal and bulbar muscular atrophy (SBMA), dentatomral-pailidoluyssan atrophy (DRPLA), Pick's disease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), frontotemporal dementia, Parkinson's disease, parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer's disease, and Friedreich ataxia (FA).

Rehabilitation for ataxia study: protocol for a randomised controlled trial of an outpatient and supported home-based physiotherapy programme for people with hereditary cerebellar ataxia

Sarah C Milne1, Louise A Corben, Melissa Roberts, David Szmulewicz, J Burns, Anneke C Grobler, Shannon Williams, Jillian Chua, Christina Liang, Phillipa J Lamont, Alison C Grootendorst, Libby Massey, Carolyn Sue, Kim Dalziel, Desiree LaGrappe, Liz Willis, Aleka Freijah, Paul Gerken, Martin B Delatycki. BMJ Open 2020;10:e040230. doi: 10.1136/bmjopen-2020-040230

Emerging evidence indicates that rehabilitation can improve ataxia, mobility and independence in everyday activities in individuals with hereditary cerebellar ataxia. However, with the rarity of the genetic ataxias and known recruitment challenges in rehabilitation trials, most studies have been underpowered, non-randomised or non-controlled. This study will be the first, appropriately powered randomised controlled trial to examine the efficacy of an outpatient and home-based rehabilitation programme on improving motor function for individuals with hereditary cerebellar ataxia.

Effects of Fe2+/Fe3+ Binding to Human Frataxin and Its D122Y Variant, as Revealed by Site-Directed Spin Labeling (SDSL) EPR Complemented by Fluorescence and Circular Dichroism Spectroscopies

Doni, D.; Passerini, L.; Audran, G.; Marque, S.R.A.; Schulz, M.; Santos, J.; Costantini, P.; Bortolus, M.; Carbonera, Int. J. Mol. Sci. 2020, 21, 9619. doi:10.3390/ijms21249619 

 The data reported in this study reveal that the currently reported binding stoichiometries should be taken with caution. The use of a spin label resistant to reduction, as well as the comparison of the binding effect of Fe2+ in wild type and in the pathological D122Y variant of frataxin, allowed us to characterize the Fe2+ binding properties of different protein sites and highlight the effect of the D122Y substitution on the surrounding residues. We suggest that both Fe2+ and Fe3+ might play a relevant role in the context of the proposed FXN physiological functions.

Minoryx’s clinical candidate leriglitazone shows clinical benefit in a proof of concept Phase 2 study in Friedreich´s ataxia

Mataró, Barcelona, Spain, December 15, 2020 - Minoryx Therapeutics, a Phase 3 clinical stage biotech company focused on the development of differentiating treatment options in orphan central nervous system (CNS) disorders, today announces topline results from the Phase 2 FRAMES clinical trial. “Clinical results from the Minoryx Phase 2 FRAMES clinical trial are promising. Specifically, the reduction in decline in upper limb ataxia in Friedreich's ataxia patients demonstrate the potential of meaningful benefit in tackling this neurodegenerative condition,” said Professor Alexandra Durr, the principal investigator and coordinator of the FRAMES study, from the Brain and Spine Institute of La Pitié-Salpêtrière University Hospital (ICM), Paris.

Calcitriol increases frataxin levels and restores mitochondrial function in cell models of Friedreich Ataxia

Elena Britti; Fabien Delaspre; Arabela Sanz; Marta Medina-Carbonero; Marta Llovera; Rosa Purroy; Stefka Mincheva-Tasheva; Jordi Tamarit; Joaquim Ros; Biochem J BCJ20200331. doi: 10.1042/BCJ20200331

We provide data that calcitriol supplementation, used at nanomolar concentrations, is able to reverse the molecular and cellular markers altered in DRG neurons. Calcitriol is able to recover both ferredoxin 1 and NCLX levels and restores mitochondrial membrane potential indicating an overall mitochondrial function improvement. Accordingly, reduction of apoptotic markers and neurite degeneration was observed and, as a result, cell survival was also recovered. All these beneficial effects would be explained by the finding that calcitriol is able to increase the mature frataxin levels in both, frataxin-deficient DRG neurons and cardiomyocytes; remarkably, this increase also occurs in lymphoblastoid cell lines derived from FA patients. In conclusion, these results provide molecular bases to consider calcitriol for an easy and affordable therapeutic approach for FA patients.

Thioredoxin and Glutaredoxin Systems as Potential Targets for the Development of New Treatments in Friedreich’s Ataxia

Seco-Cervera, M.; González-Cabo, P.; Pallardó, F.V.; Romá-Mateo, C.; García-Giménez, J.L. ; Antioxidants 2020, 9, 1257. doi:10.3390/antiox9121257 The thioredoxin family consists of a small group of redox proteins present in all organisms and composed of thioredoxins (TRXs), glutaredoxins (GLRXs) and peroxiredoxins (PRDXs) which are found in the extracellular fluid, the cytoplasm, the mitochondria and in the nucleus with functions that include antioxidation, signaling and transcriptional control, among others. The importance of thioredoxin family proteins in neurodegenerative diseases is gaining relevance because some of these proteins have demonstrated an important role in the central nervous system by mediating neuroprotection against oxidative stress, contributing to mitochondrial function and regulating gene expression. Specifically, in the context of Friedreich’s ataxia (FRDA), thioredoxin family proteins may have a special role in the regulation of Nrf2 expression and function, in Fe-S cluster metabolism, controlling the expression of genes located at the iron-response element (IRE) and probably regulating ferroptosis. Therefore, comprehension of the mechanisms that closely link thioredoxin family proteins with cellular processes affected in FRDA will serve as a cornerstone to design improved therapeutic strategies.

Friedreich’s Ataxia Center of Excellence at CHOP Awarded $1.275 Million to Advance Medical Research

Published on Dec 10, 2020 in CHOP News. The Friedreich’s Ataxia Center of Excellence (COE) at Children’s Hospital of Philadelphia (CHOP) was awarded $1.275 million by the Friedreich’s Ataxia Research Alliance (FARA), along with the Hamilton and Finneran families and the CureFA Foundation, to support the development of breakthrough therapies to improve the quality of life for individuals with Friedreich’s ataxia. The Friedreich’s Ataxia COE at CHOP was established in March 2014 by CHOP, Penn Medicine and FARA, and was a result of a $3.25 million gift from FARA in partnership with the Hamilton and Finneran families. Since 2014, more than $8 million in research funding has been committed to the COE to create a multi-disciplinary, translational research and clinical care center devoted to FA. Its mission is to expedite basic science and drug discovery to treatments and dedicate resources to clinical research and care to improve outcomes for individuals living with FA.

Safety and feasibility of upper limb cardiopulmonary exercise test in Friedreich ataxia

Chiara Pane, Andrea Salzano, Assunta Trinchillo, Claudia Del Prete, Carlo Casali, Christian Marcotulli, Giovanni Defazio, Vincenzo Guardasole, Rossella Vastarella, Francesco Giallauria, Giorgia Puorro, Angela Marsili, Giovanna De Michele, Alessandro Filla, Antonio Cittadini, Francesco Saccà; European Journal of Preventive Cardiology, zwaa134, doi:10.1093/eurjpc/zwaa134 

 Upper limb CPET is useful in the assessment of exercise tolerance and a possible tool to determine the functional severity of the mitochondrial oxidative defect in patients with FRDA. The cardiopulmonary exercise test is an ideal functional endpoint for Phases II and III trials through a simple, non-invasive, and safe exercise test.