Potential biomarker identification for Friedreich’s ataxia using overlapping gene expression patterns in patient cells and mouse dorsal root ganglion

Marissa Z. McMackin, Blythe Durbin-Johnson, Marek Napierala, Jill S. Napierala, Luis Ruiz, Eleonora Napoli, Susan Perlman, Cecilia Giulivi, Gino A. Cortopassi (2019) . PLoS ONE 14(10): e0223209. doi:10.1371/journal.pone.0223209

Friedreich’s ataxia (FA) is a neurodegenerative disease with no approved therapy that is the result of frataxin deficiency. The identification of human FA blood biomarkers related to disease severity and neuro-pathomechanism could support clinical trials of drug efficacy. To try to identify human biomarkers of neuro-pathomechanistic relevance, we compared the overlapping gene expression changes of primary blood and skin cells of FA patients with changes in the Dorsal Root Ganglion (DRG) of the KIKO FA mouse model. As DRG is the primary site of neurodegeneration in FA, our goal was to identify which changes in blood and skin of FA patients provide a 'window' into the FA neuropathomechanism inside the nervous system. In addition, gene expression in frataxin-deficient neuroglial cells and FA mouse hearts were compared for a total of 5 data sets. The overlap of these changes strongly supports mitochondrial changes, apoptosis and alterations of selenium metabolism. Consistent biomarkers were observed, including three genes of mitochondrial stress (MTIF2, ENO2), apoptosis (DDIT3/CHOP), oxidative stress (PREX1), and selenometabolism (SEPW1). These results prompted our investigation of the GPX1 activity as a marker of selenium and oxidative stress, in which we observed a significant change in FA patients. We believe these lead biomarkers that could be assayed in FA patient blood as indicators of disease severity and progression, and also support the involvement of mitochondria, apoptosis and selenium in the neurodegenerative process.

PTC Therapeutics Reports Third Quarter 2019 Financial Results and Provides a Corporate Update

SOUTH PLAINFIELD, N.J., Oct. 29, 2019 /PRNewswire/ -- PTC Therapeutics, Inc. (NASDAQ: PTCT) today announced a corporate update and reported financial results for the third quarter ending September 30, 2019.

The Friedreich ataxia program continues to advance with an IND submission now expected in mid-2020.

Symposium updates Friedreich’s ataxia community on advances against FA

Written by Anne DeLotto Baier · October 29, 2019 @ 12:55 pm · Filed under Hot News, Morsani College of Medicine, Neurosciences & Brain Repair, Patient Care, Research, School of Biomedical Sciences.

Less than three weeks after the 10th annual Friedreich’s Ataxia (FA) Scientific Symposium at USF, Reata Pharmaceuticals Inc. announced that its MOXIe trial of daily therapy with omaveloxolone capsules (RTA 408) improved the neurological function of patients with FA – a rare, debilitating and life-shortening neuromuscular disorder.

Predictors of Left Ventricular Dysfunction in Friedreich’s Ataxia in a 16-Year Observational Study

Lise Legrand, Abdourahmane Diallo, Marie-Lorraine Monin, Claire Ewenczyk, Perrine Charles, Richard Isnard, Eric Vicaut, Gilles Montalescot, Alexandra Durr, Francoise Pousset; Am J Cardiovasc Drugs (2019). doi:10.1007/s40256-019-00375-z

Echocardiographic follow-up combined with size assessment of GAA repeat expansions is a powerful tool to identify patients at high risk of developing LV systolic dysfunction up to 5 years before clinical symptoms. Further studies are mandatory to investigate if these patients would benefit from cardiac interventions.

Ironing the mitochondria: Relevance to its dynamics

Mamta Upadhyay, Saloni Agarwal, Mitochondrion, 2019, doi:10.1016/j.mito.2019.09.007.

The mitochondrion is “jack of many trades and master of one”. Despite being a master in energy generation, it plays a significant role in other cellular processes, including calcium homeostasis, cell death, and iron metabolism. Since mitochondria employ the majority of cellular iron, it plays a central role in the iron homeostasis. Iron could be a major regulator of mitochondrial dynamics as the excess of iron leads to oxidative stress, which causes a disturbance in mitochondrial dynamics. Remarkably, abnormal iron accumulation has been observed in the brain regions of the neurodegenerative disorders patients. These neurodegenerative disorders are also often associated with the abnormal mitochondrial dynamics. Here in this article, we will mainly discuss the studies focused on unravelling the role of iron in mitochondrial dynamics.

Cerebellum and cognition in Friedreich ataxia: a voxel-based morphometry and volumetric MRI study

Sirio Cocozza, Te*resa Costabile, Giuseppe Pontillo, Maria Lieto, Camilla Russo, I Leonardo Radice,Chiara Pane, Alessandro Filla, Arturo Brunetti, Francesco Saccà; J Neurol (2019). doi:10.1007/s00415-019-09582-9

With two different image analysis techniques, we confirmed the presence of cerebellar volume loss in FRDA, mainly affecting the posterior lobe. In particular, Lobule IX atrophy correlated with worse visuo-spatial abilities, further expanding our knowledge about the physiopathology of cognitive impairment in FRDA.

Ethical, legal, and social issues (ELSI) in rare diseases: a landscape analysis from funders

Adam L. Hartman, Anneliene Hechtelt Jonker, Melissa A. Parisi, Daria Julkowska, Nicole Lockhart & Rosario Isasi ; Eur J Hum Genet. 2019 Sep 19. doi: 10.1038/s41431-019-0513-3.

Recent interest in personalized medicine has highlighted the importance of research in ethical, legal, and social issues (ELSI). Issues in ELSI research may be magnified in the rare diseases population (i.e., small numbers of affected individuals, challenges in maintaining confidentiality, and paucity of treatments for diseases where natural history information may be limited). More than other areas of research, potential barriers include the lack of funding opportunities and appropriate review processes for applications to funding agencies. The ELSI Working Group of the International Rare Diseases Research Consortium (IRDiRC) performed an informal survey on ELSI funding initiatives to learn more about different funding mechanisms and to identify potential gaps in funding opportunities. The Working Group discusses these challenges and highlights the role of funding agencies and partners such as patient advocacy groups, specialists in social sciences and humanities, and clinicians to advance ELSI research in rare diseases.

PTC Therapeutics enters collaboration with Aldevron to support GMP plasmid manufacturing

South Plainfield, New Jersey. Thursday, October 10, 2019.

PTC Therapeutics, global biopharmaceutical company, announced a collaboration with Aldevron, LLC to secure GMP manufacturing capacity for PTC's gene therapy portfolio, including the Friedreich ataxia and Angelman syndrome programmes in PTC's growing gene therapy pipeline.

The central nervous system (CNS) gene therapy platform at PTC uses targeted micro-dosing applied directly to areas involved in the disorder. This allows for greater efficacy, durability, lower risk of immunogenicity or other off-target effect, and efficient and scalable manufacturing. PTC has an advancing gene therapy pipeline for CNS disorders, including programs for AADC deficiency, Friedreich Ataxia, and Angelman Syndrome. PTC is preparing a BLA for the treatment of AADC deficiency for submission to the FDA in the fourth quarter of 2019.

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

Petrillo, S.; D’Amico, J.; La Rosa, P.; Bertini, E.S.; Piemonte, F. Int. J. Mol. Sci. 2019, 20, 5211. Doi:10.3390/ijms20205211 (registering DOI)

Different redox drugs, joined by their ability to modulate the NRF2 pathway, elicit differential response profiles in FRDA fibroblasts. Using drugs aimed at preventing inflammation (SFN, NAC), lipid peroxidation (DMF, OMAV, and EPI-743), or redox imbalance (SFN), “multi-target” synergic therapies can be developed in FRDA, based on the patient’s clinical conditions and therapeutic needs.

Safety and Biodistribution of Human Bone Marrow-Derived Mesenchymal Stromal Cells Injected Intrathecally in Non-Obese Diabetic Severe Combined Immunodeficiency Mice: Preclinical Study

Mari Paz Quesada, David García-Bernal, Diego PastorAlicia Estirado, Miguel Blanquer, Ana Mª García-HernándezJosé, M. Moraleda, Salvador Martínez. Eng Regen Med (2019) 16: 525. doi:10.1007/s13770-019-00202-1

Mesenchymal stromal cells (MSCs) have potent immunomodulatory and neuroprotective properties, and have been tested in neurodegenerative diseases resulting in meaningful clinical improvements. Regulatory guidelines specify the need to perform preclinical studies prior any clinical trial, including biodistribution assays and tumourigenesis exclusion. We conducted a preclinical study of human bone marrow MSCs (hBM-MSCs) injected by intrathecal route in Non-Obese Diabetic Severe Combined Immunodeficiency mice, to explore cellular biodistribution and toxicity as a privileged administration method for cell therapy in Friedreich’s Ataxia.

Protocol of a randomized, double-blind, placebo-controlled, parallel-group, multicentre study of the efficacy and safety of nicotinamide in patients with Friedreich ataxia (NICOFA)

Kathrin Reetz, Ralf-Dieter Hilgers, Susanne Isfort, Marc Dohmen, Claire Didszun, Kathrin Fedosov, Jennifer Kistermann, Caterina Mariotti, Alexandra Durr, Sylvia Boesch, Thomas Klopstock, Francisco Javier Rodríguez de Rivera Garrido, Ludger Schöls, Thomas Klockgether, Massimo Pandolfo, Rudolf Korinthenberg, Philip Lavin, Geert Molenberghs, Vincenzo Libri, Paola Giunti, Richard Festenstein, Jörg B. Schulz & the EFACTS or NICOFA study group. Neurological Research and Practice volume 1, Article number: 33 (2019) doi:10.1186/s42466-019-0038-9


Currently, no treatment that delays with the progression of Friedreich ataxia is available. In the majority of patients Friedreich ataxia is caused by homozygous pathological expansion of GAA repeats in the first intron of the FXN gene. Nicotinamide acts as a histone deacetylase inhibitor. Dose escalation studies have shown, that short term treatment with dosages of up to 4 g/day increase the expression of FXN mRNA and frataxin protein up to the levels of asymptomatic heterozygous gene carriers. The long-term effects and the effects on clinical endpoints, activities of daily living and quality of life are unknown.

MINORYX THERAPEUTICS RECEIVES FDA ORPHAN DRUG DESIGNATION FOR LERIGLITAZONE IN FRIEDREICH’S ATAXIA

17 October, 2019.
Mataró, Barcelona, Spain and Charleroi, Belgium, October 17, 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 in Friedreich’s Ataxia by the US Food and Drug Administration (FDA).

Management Call to Discuss Positive Topline Pivotal MOXIe Data

Reata Pharmaceuticals, OCT 2019

Management Call to Discuss Positive Topline Pivotal MOXIe Data

Orphan Drugs In Development For The Treatment Of Friedreich’s Ataxia: Focus On Omaveloxolone

Shaila D Ghanekar, Wai Wai Miller, Colin J Meyer, Kevin J Fenelon, Alvin Lacdao, Theresa A Zesiewicz; Degenerative Neurological and Neuromuscular Disease 15 October 2019 Volume 2019:9 Pages 103—107 doi:10.2147/DNND.S180027

Investigations into the pathological mechanisms of FRDA have revealed the central role of frataxin deficiency and the subsequent lack of transcription factor Nrf2. Consequently, the Nrf2 activators discussed here as well as the several treatments in development focus on reversing the oxidative stress environment caused by frataxin deficiency. While the discussed orphan drugs show promise in the treatment of FRDA, further investigations must be conducted in order to ensure the efficacy and safety of such drugs, as well as to determine even more therapeutic options.

Reata Announces Positive Topline Results from the MOXIe Registrational Trial of Omaveloxolone in Patients with Friedreich’s Ataxia

ACHIEVED PRIMARY ENDPOINT OF STATISTICALLY SIGNIFICANT IMPROVEMENT IN MFARS COMPARED TO PLACEBO AFTER 48 WEEKS OF TREATMENT

CONFERENCE CALL WITH MANAGEMENT SCHEDULED FOR OCTOBER 15, 2019, AT 8:00 AM ET

IRVING, Texas, Oct. 14, 2019 (GLOBE NEWSWIRE) -- Reata Pharmaceuticals, Inc. (Nasdaq: RETA), a clinical-stage biopharmaceutical company, announced today that the registrational Part 2 portion of the MOXIe Phase 2 trial of omaveloxolone in patients with Friedreich’s ataxia (FA) met its primary endpoint of change in the modified Friedreich’s Ataxia Rating Scale (mFARS) relative to placebo after 48 weeks of treatment. Patients treated with omaveloxolone (150 mg/day) demonstrated a statistically significant, placebo-corrected 2.40 point improvement in mFARS after 48 weeks of treatment (p=0.014). Omaveloxolone treatment was generally reported to be well-tolerated. Based on these positive results, and subject to discussions with regulatory authorities, the company plans to proceed with the submission of regulatory filings for marketing approval in the United States and internationally.

Iron–Sulfur Cluster Metabolism Impacts Iron Homeostasis, Ferroptosis Sensitivity, and Human Disease

Vladislav O. SviderskiyErdem M. TerziRichard Possemato, Ferroptosis in Health and Disease. Springer, Cham. doi:10.1007/978-3-030-26780-3_12

We ask whether dysregulation of ISC synthesis, observed in multiple pathological settings including neurodegenerative diseases such as Friedreich’s Ataxia, sideroblastic anemia, and cancer, leads to pathology as a result of ferroptosis.

Reata Pharmaceuticals Reacquires Rights From AbbVie to Develop and Commercialize Bardoxolone Methyl, Omaveloxolone, and All Next-Generation Nrf2 Activators

IRVING, Texas, Oct. 10, 2019 (GLOBE NEWSWIRE) — Reata Pharmaceuticals, Inc. (Nasdaq: RETA), a clinical-stage biopharmaceutical company, today announced the reacquisition of development, manufacturing and commercialization rights concerning its proprietary Nrf2 activator product platform originally licensed to AbbVie, Inc. (AbbVie) for territories outside of the United States with respect to bardoxolone methyl (bardoxolone) and worldwide with respect to omaveloxolone and other next-generation Nrf2 activators. As a result, Reata now possesses exclusive, worldwide rights to develop, manufacture and commercialize bardoxolone methyl (bardoxolone), omaveloxolone, and all other next-generation Nrf2 activators, excluding certain Asian markets for bardoxolone which are licensed to Kyowa Kirin Co., Ltd.

Induced pluripotent stem cells-derived neurons from patients with Friedreich ataxia exhibit differential sensitivity to resveratrol and nicotinamide

Pauline Georges, Maria-Gabriela Boza-Moran, Jacqueline Gide, Georges Arielle Pêche, Benjamin Forêt, Aurélien Bayot, Pierre Rustin, Marc Peschanski, Cécile Martinat & Laetitia Aubry ; Scientific Reports volume 9, Article number: 14568 (2019) doi:10.1038/s41598-019-49870-y

By comparing the effects of both molecules on different cell types that may be considered to be non-relevant for the disease, such as fibroblasts, or more relevant to the disease, such as neurons differentiated from iPSCs, a differential response was observed; this response suggests the importance of developing more predictive in vitro systems for drug discovery. Our results demonstrate the value of utilizing human iPSCs early in drug discovery to improve translational predictability.

Minoryx Therapeutics termine le recrutement de FRAMES, son essai clinique de phase 2 du leriglitazone dans l’ataxie de Friedreich

Mataró, Barcelone, Espagne et Charleroi, Belgique, le 8 octobre 2019 - MinoryxTherapeutics, une société spécialisée dans le développement de traitements innovants contredes maladies orphelines du système nerveux central (SNC), annonce aujourd’hui avoirterminé le recrutement des patients dans son essai clinique de phase 2 FRAMES sur l’ataxiede Friedreich avec son candidat médicament leriglitazone (MIN-102), un nouvel agoniste du PPARγ.

L’essai FRAMES est une étude multicentrique et randomisée, en double-aveugle contreplacebo, qui vise à évaluer l’efficacité et l’innocuité du leriglitazone chez les patients souffrantd’ataxie de Friedreich. Le recrutement de 39 patients dans quatre pays européens a été réalisé au cours des derniers quatre mois et demi en avance sur les prévisions. Les patients, âgés de 12 à 60 ans, vont recevoir durant un an une dose quotidienne de leriglitazone en suspension orale. L’objectif principal de l’essai consiste à évaluer l’effet du candidat médicament sur la progression de la maladie. Cet effet sera mesuré par imagerie de pointe de la moëlle épinière. Les objectifs secondaires incluent l’innocuité et la tolérance, l’effet sur d’autres observations cliniques, telles que les retours des patients, l’échelle d’incapacité fonctionnelle et les biomarqueurs exploratoires.

Minoryx completa el reclutamiento del ensayo clínico de Fase II de leriglitazona para la ataxia de Friedreich

Mataró (Barcelona)-Charleroi (Bélgica), 8 de octubre de 2019. Minoryx Therapeutics, compañía especializada en el desarrollo de tratamientos innovadores para las enfermedades huérfanas del sistema nervioso central (SNC), anuncia hoy que ha completado el reclutamiento de pacientes en el ensayo clínico FRAMES de Fase II de su fármaco leriglitazona (MIN-102) para la ataxia de Friedreich (FRDA).

FRAMES es un ensayo multicéntrico, aleatorio, doble ciego y controlado con placebo que evaluará la eficacia y la seguridad de leriglitazona en pacientes con FRDA. En total se han reclutado a 39 pacientes en cuatro países europeos en solo cuatro meses y medio, mucho antes de lo previsto. Los pacientes, que tienen entre 12 y 60 años, recibirán leriglitazona administrada una vez al día por vía oral durante un año. El objetivo principal del ensayo es controlar el efecto sobre la progresión de la enfermedad, que se medirá mediante imágenes de resonancia magnética de última generación de la médula espinal. Los objetivos secundarios incluyen la seguridad y tolerabilidad.

MINORYX THERAPEUTICS COMPLETES ENROLLMENT IN FRAMES PHASE 2 TRIAL WITH LERIGLITAZONE IN FRIEDREICH’S ATAXIA

Mataró, Barcelona, Spain and Charleroi, Belgium, October 8, 2019.

Minoryx Therapeutics, a company specializing in the development of innovative treatments for orphan central nervous system (CNS) diseases, today announces that it has completed recruitment in the FRAMES phase 2 clinical trial of its novel PPARγ agonist, leriglitazone (MIN-102), in patients with Friedreich’s Ataxia.

FRAMES is a multicenter, randomized, double-blind, placebo-controlled trial that will assess the efficacy and safety of leriglitazone in patients with Friedreich’s Ataxia. Recruitment of 39 patients in four European countries was completed in just four and a half months, well ahead of schedule. The patients, aged 12-60 years, will receive leriglitazone, administered once a day as an oral suspension, for a total of one year. The primary objective of the trial is to monitor the effect on disease progression. This will be measured through state-of-the art imaging of the spinal cord. Secondary objectives include safety and tolerability, effect on additional clinical measures, such as patient reported outcomes, functional disability scores and exploratory biomarkers.

Primary Cultures of Pure Embryonic Dorsal Root Ganglia Sensory Neurons as a New Cellular Model for Friedreich’s Ataxia

Griso O., Puccio H. (2020). In: Richard GF. (eds) Trinucleotide Repeats. Methods in Molecular Biology, vol 2056. Humana, New York, NY. doi:10.1007/978-1-4939-9784-8_15

We have established a model of primary cultures of DRG sensory neurons in which we induce the loss of the frataxin protein. With such a model we can alleviate the issues related to the complexity of DRG tissues and low amount of sensory neuron material in adult mouse. Hereby, we provide a protocol of detailed and optimized methods to obtain high yield of healthy mouse DRG sensory neuron in culture.

SINEUP non-coding RNAs rescue defective frataxin expression and activity in a cellular model of Friedreich's Ataxia

Carlotta Bon, Riccardo Luffarelli, Roberta Russo, Silvia Fortuni, Bianca Pierattini, Chiara Santulli, Cristina Fimiani, Francesca Persichetti, Diego Cotella, Antonello Mallamaci, Claudio Santoro, Piero Carninci, Stefano Espinoza, Roberto Testi, Silvia Zucchelli, Ivano Condò, Stefano Gustincich; Nucleic Acids Research, , gkz798, doi:10.1093/nar/gkz798

We have previously described SINEUPs, natural and synthetic antisense long non-coding RNAs, which promote translation of partially overlapping mRNAs through the activity of an embedded SINEB2 domain. Here, by in vitro screening, we have identified a number of SINEUPs targeting human FXN mRNA and capable to up-regulate frataxin protein to physiological amounts acting at the post-transcriptional level. Furthermore, FXN-specific SINEUPs promote the recovery of disease-associated mitochondrial aconitase defects in FRDA-derived cells. In summary, we provide evidence that SINEUPs may be the first gene-specific therapeutic approach to activate FXN translation in FRDA and, more broadly, a novel scalable platform to develop new RNA-based therapies for haploinsufficient diseases.

A case of Friedreich ataxia in an adolescent with 16p11.2 microdeletion syndrome

Valentina Pelliccia, Silvia Ferranti, Rosa Mostardini, Salvatore Grosso; Neurol Sci (2019). doi:10.1007/s10072-019-04075-z

A completely different genetic mechanism is the one responsible for Friedreich ataxia; the disorder is provoked by an unstable expansion of the GAA triplet located in the frataxin gene [4]. Friedreich ataxia is the most common type of inherited ataxia; onset of symptoms usually occurs during adolescence, and clinical course is slowly progressive. The main clinical signs include gait imbalance, abnormal eye movements, scoliosis, feet deformities, urinary dysfunction, and cardiac involvement.