Efficacy and Safety of Leriglitazone in Patients With Friedreich Ataxia: A Phase 2 Double-Blind, Randomized Controlled Trial (FRAMES).
Pandolfo M, Reetz K, Darling A, Rodriguez de Rivera FJ, Henry PG, Joers J, Lenglet C, Adanyeguh I, Deelchand D, Mochel F, Pousset F, Pascual S, Van den Eede D, Martin-Ugarte I, Vilà-Brau A, Mantilla A, Pascual M, Martinell M, Meya U, Durr A.
In this double-blind, randomized controlled trial, the authors assessed effects of leriglitazone, a selective peroxisome proliferator-activated receptor γ agonist, in patients with FRDA. The primary endpoint of change in spinal cord area was not met. Secondary endpoints - iron accumulation in the dentate nucleus and tNAA/mIns ratio - provide support for leriglitazone’s mode of action and for larger studies in patients with FRDA.
Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.
Pellerin D, Danzi MC, Wilke C, Renaud M, Fazal S, Dicaire MJ, Scriba CK, Ashton C, Yanick C, Beijer D, Rebelo A, Rocca C, Jaunmuktane Z, Sonnen JA, Larivière R, Genís D, Molina Porcel L, Choquet K, Sakalla R, Provost S, Robertson R, Allard-Chamard X, Tétreault M, Reiling SJ, Nagy S, Nishadham V, Purushottam M, Vengalil S, Bardhan M, Nalini A, Chen Z, Mathieu J, Massie R, Chalk CH, Lafontaine AL, Evoy F, Rioux MF, Ragoussis J, Boycott KM, Dubé MP, Duquette A, Houlden H, Ravenscroft G, Laing NG, Lamont PJ, Saporta MA, Schüle R, Schöls L, La Piana R, Synofzik M, Zuchner S, Brais B.
In this study a dominantly inherited deep intronic GAA repeat expansion in FGF14 was found to be associated with Late-Onset Cerebellar Ataxia in two independent case-control series - one French Canadian and the other German - and in an Australian and Indian cohort.
An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14.
Rafehi H, Read J, Szmulewicz DJ, Davies KC, Snell P, Fearnley LG, Scott L, Thomsen M, Gillies G, Pope K, Bennett MF, Munro JE, Ngo KJ, Chen L, Wallis MJ, Butler EG, Kumar KR, Wu KH, Tomlinson SE, Tisch S, Malhotra A, Lee-Archer M, Dolzhenko E, Eberle MA, Roberts LJ, Fogel BL, Brüggemann N, Lohmann K, Delatycki MB, Bahlo M, Lockhart PJ.
In this study, the authors identified an intronic GAA repeat expansion in fibroblast growth factor 14 (FGF14) as a frequent cause of adult-onset ataxia.
Overall Role of Contactins Expression in Neurodevelopmental Events and Contribution to Neurological Disorders.
Bizzoca A, Jirillo E, Flace P, Gennarini G.
This study supports the significance of changes in morphoregulatory proteins expression in FA pathogenesis and the potential of antioxidant administration as a therapeutic approach.
Systemic administration of novel engineered AAV capsids facilitates enhanced transgene expression in the macaque CNS.
Stanton AC, Lagerborg KA, Tellez L, Krunnfusz A, King EM, Ye S, Solomon IH, Tabebordbar M, Sabeti PC.
In this study, the investigators use an mRNA-based directed-evolution strategy in multiple strains of mice as well as a de novo selection in cynomolgus macaques to identify families of engineered vectors with increased potency in the brain and decreased tropism for the liver. The results highlight the critical need for using appropriate animal models to both identify and evaluate novel AAVs intended for delivery to the human central nervous system.
The mutational dynamics of short tandem repeats in large, multigenerational families.
Steely CJ, Watkins WS, Baird L, Jorde LB.
This study investigates the genome-wide pattern of mutations at short tandem repeat loci.
Double blind trial of a deuterated form of linoleic acid (RT001) in Friedreich ataxia.
Lynch DR, Mathews KD, Perlman S, Zesiewicz T, Subramony S, Omidvar O, Vogel AP, Krtolica A, Litterman N, van der Ploeg L, Heerinckx F, Milner P, Midei M.
This study tested the ability of RT001, a deuterated form of linoleic acid (D2-LA), to alter disease severity in patients with FRDA in a double-blind placebo-controlled trial. No significant changes in the primary outcome measure (maximum oxygen consumption during cardiopulmonary exercise testing) were observed for RT001 compared to placebo. Similarly, no differences between the groups were found in secondary or exploratory outcome measures.
S-Glutathionylation and S-Nitrosylation in Mitochondria: Focus on Homeostasis and Neurodegenerative Diseases.
Vrettou S, Wirth B.
Herein, the authors discuss how S-glutathionylation and S-nitrosylation interfere in mitochondrial homeostasis and how the deregulation of these modifications is associated with Alzheimer's, Parkinson's, amyotrophic lateral sclerosis and Friedreich's ataxia.
Ataxia Rating Scales: Content Analysis by Linking to the International Classification of Functioning, Disability and Health.
Etoom M, Jahan AM, Alghwiri A, Lena F, Modugno N.
The aim of the study was to analyze and compare the content of the recommended ataxia rating scales - scale for assessment and rating of ataxia (SARA), international cooperative ataxia rating scales, Friedreich's ataxia rating scale (FARS), and unified multiple system atrophy rating scale (UMSARS) - by linking them to the international classification of functioning, disability and health (ICF).
Retinal and Visual Pathways Involvement in Carriers of Friedreich's Ataxia.
Ziccardi L, Barbano L, Antonelli G, Cioffi E, Di Renzo A, Gioiosa V, Marcotulli C, Grzybowski A, Casali C, Parisi V.
This study analyzes the morpho-functional condition of the retina and of the optic pathways in healthy heterozygous carriers of Friedreich's ataxia (C-FRDA). In C-FRDA, a dysfunction of retinal elements without morphological macular impairment and a morphological impairment of RNFL associated with an abnormal neural conduction along the visual pathways can be detected.
Mitochondrial Calcium Homeostasis in the Pathology and Therapeutic Application in Friedreich's Ataxia.
Zhao H, Li Z, Liu Y, Zhang M, Li K.
This paper reviews the use of drugs targeting Ca2+ homeostasis in FA preclinical models.
Astrocytic mitochondrial frataxin-A promising target for ischemic brain injury.
Hazra R, Novelli EM, Hu X.
This review addresses the role of frataxin in activated astrocytes during ischemia.
