Riccardo Turchi, Flavia Tortolici, Giulio Guidobaldi, Federico Iacovelli, Mattia Falconi, Stefano Rufini, Raffaella Faraonio, Viviana Casagrande, Lorenzo De Angelis, Massimo Federici, Simone Carotti, Maria Francesconi, Maria Zingariello, Sergio Morini, Roberta Bernardini, Maurizio Mattei, Daniele Lettieri-Barbato, Katia Aquilano; bioRxiv 664649; doi:10.1101/664649
Decreased expression of the mitochondrial protein frataxin (FXN) causes Friedreich's ataxia (FRDA). FRDA is a neurodegenerative disease also characterized by systemic metabolic alterations that increase the risk of developing type 2 diabetes thus aggravating FRDA prognosis. Brown adipose tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that, in addition to its thermoregulatory role, turns excess energy into heat to maintain energy balance. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows reduced energy expenditure and VO2, hyperlipidemia, decreased insulin sensitivity and enhanced circulating levels of leptin, recapitulating diabetes-like signatures. FXN deficiency leads to alteration of mitochondrial structure and oxygen consumption, decreased lipolysis and lipid accumulation in BAT. Transcriptomic data highlighted a blunted thermogenesis response, as several biological processes related to thermogenesis (e.g. response to temperature stimuli, mitochondrial gene transcription, triglyceride metabolism, adipogenesis) resulted affected in BAT of KIKO mice upon cold exposure. Decreased adaptation to cool temperature in association with limited PKA-mediated lipolysis and downregulation of the expression of the genes controlling mitochondrial metabolism and lipid catabolism were observed in KIKO mice. T37i brown adipocytes and primary adipocytes with FXN deficiency showed reduced thermogenesis and adipogenesis markers respectively recapitulating the molecular signatures detected in KIKO mice. Collectively our data point to BAT dysfunction in FRDA and suggest BAT as a promising target to overcome metabolic complications in FRDA.
Wednesday, June 12, 2019
Tuesday, June 11, 2019
Pharmacokinetics and pharmacodynamics of the novel Nrf2 activator omaveloxolone in primates
Reisman SA, Gahir SS, Lee CY, Proksch JW, Sakamoto M, Ward KW (Reata Pharmaceuticals, Inc., Irving, TX 75063, USA); Drug Des Devel Ther. 2019; 13: 1259–1270.Published online 2019 Apr 17. doi: 10.2147/DDDT.S193889
Overall, the monkey data demonstrate a well-characterized and dose-proportional PK and tissue distribution profile after oral administration of omaveloxolone, which was associated with Nrf2 activation. Further, systemic exposures to omaveloxolone that produce Nrf2 activation in monkeys were readily achievable in Friedreich's ataxia patients after oral administration.
Overall, the monkey data demonstrate a well-characterized and dose-proportional PK and tissue distribution profile after oral administration of omaveloxolone, which was associated with Nrf2 activation. Further, systemic exposures to omaveloxolone that produce Nrf2 activation in monkeys were readily achievable in Friedreich's ataxia patients after oral administration.
Is left ventricular longitudinal strain a good prognostic factor in Friedreich ataxia?
C. Heuze, L. Legrand, A. Diallo, M.L. Monin, C. Ewenczyk, R. Isnard, E. Vicaut, A. Durr, F. Pousset, Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 3, 2019, Page e321, doi:10.1016/j.acvdsp.2019.04.036.
GLS is a predictor of morbimortality but is not superior to LVEF in FRDA patients.
GLS is a predictor of morbimortality but is not superior to LVEF in FRDA patients.
Friday, June 7, 2019
Microvascular pathology in Friedreich cardiomyopathy
Arnulf H. Koeppen, Jiang Qian, Alicia M. Travis, Alyssa B. Sossei, Paul J. Feustel and Joseph E. Mazurkiewicz; Histol Histopathol. 2019 Jun 5:18132. doi: 10.14670/HH-18-132. [Epub ahead of print]
Heart disease is an integral part of Friedreich ataxia (FA). In addition to cardiomyocyte hypertrophy, fiber necrosis, and inflammatory infiltration, sections show fibrosis and disorganized capillaries. We examined the left ventricular wall (LVW) of 41 homozygous and 2 compound heterozygous FA patients aged 10-87 and 21 controls aged 2-69.
Heart disease is an integral part of Friedreich ataxia (FA). In addition to cardiomyocyte hypertrophy, fiber necrosis, and inflammatory infiltration, sections show fibrosis and disorganized capillaries. We examined the left ventricular wall (LVW) of 41 homozygous and 2 compound heterozygous FA patients aged 10-87 and 21 controls aged 2-69.
Wednesday, June 5, 2019
Minoryx inicia el primer tratamiento de un paciente con Ataxia de Friedreich en el Hospital La Paz
Mataró (Barcelona)-Charleroi (Bélgica), 4 de mayo de 2019. Minoryx Therapeutics, compañía biotecnológica especializada en el desarrollo de nuevos medicamentos para enfermedades huérfanas, anuncia hoy que ha dosificado con el fármaco leriglitazona (MIN-102) al primer paciente en el ensayo clínico FRAMES de Fase II para el tratamiento de la Ataxia de Friedreich (FRDA).
Minoryx Therapeutics enrôle le premier patient de son essai clinique de phase II dans l’ataxie de Friedreich
Mataró, Barcelone, Espagne et Charleroi, Belgique, le 4 juin 2019 - Minoryx Therapeutics, une société spécialisée dans le développement de nouveaux médicaments contre des maladies orphelines, annonce aujourd'hui qu’un premier dosage de patient a été réalisé dans l’essai clinique FRAMES de phase II sur l’ataxie de Friedreich avec son candidat médicament leriglitazone (MIN-102).
Minoryx Therapeutics announces first patient dosed in the FRAMES phase 2 trial in Friedreich’s Ataxia
Minoryx Therapeutics, a company specializing in the development of new drugs for orphan diseases, today announces that the first patient has been dosed with its lead candidate, leriglitazone (MIN-102), in the phase 2 FRAMES clinical trial in Friedreich’s Ataxia.
Tuesday, June 4, 2019
Dimethyl fumarate dosing in humans increases frataxin expression: A potential therapy for Friedreich’s Ataxia
Mittal Jasoliya , Francesco Sacca , Sunil Sahdeo, Frederic Chedin, Chiara Pane, Vincenzo Brescia Morra, Alessandro Filla, Mark Pook, Gino Cortopassi. PLoS ONE 14(6): e0217776. doi:10.1371/journal.pone.0217776
Friedreich’s Ataxia (FA) is an inherited neurodegenerative disorder resulting from decreased expression of the mitochondrial protein frataxin, for which there is no approved therapy. High throughput screening of clinically used drugs identified Dimethyl fumarate (DMF) as protective in FA patient cells. Here we demonstrate that DMF significantly increases frataxin gene (FXN) expression in FA cell model, FA mouse model and in DMF treated humans. DMF also rescues mitochondrial biogenesis deficiency in FA-patient derived cell model. We further examined the mechanism of DMF's frataxin induction in FA patient cells. It has been shown that transcription-inhibitory R-loops form at GAA expansion mutations, thus decreasing FXN expression. In FA patient cells, we demonstrate that DMF significantly increases transcription initiation. As a potential consequence, we observe significant reduction in both R-loop formation and transcriptional pausing thereby significantly increasing FXN expression. Lastly, DMF dosed Multiple Sclerosis (MS) patients showed significant increase in FXN expression by ~85%. Since inherited deficiency in FXN is the primary cause of FA, and DMF is demonstrated to increase FXN expression in humans, DMF could be considered for Friedreich's therapy.
Friedreich’s Ataxia (FA) is an inherited neurodegenerative disorder resulting from decreased expression of the mitochondrial protein frataxin, for which there is no approved therapy. High throughput screening of clinically used drugs identified Dimethyl fumarate (DMF) as protective in FA patient cells. Here we demonstrate that DMF significantly increases frataxin gene (FXN) expression in FA cell model, FA mouse model and in DMF treated humans. DMF also rescues mitochondrial biogenesis deficiency in FA-patient derived cell model. We further examined the mechanism of DMF's frataxin induction in FA patient cells. It has been shown that transcription-inhibitory R-loops form at GAA expansion mutations, thus decreasing FXN expression. In FA patient cells, we demonstrate that DMF significantly increases transcription initiation. As a potential consequence, we observe significant reduction in both R-loop formation and transcriptional pausing thereby significantly increasing FXN expression. Lastly, DMF dosed Multiple Sclerosis (MS) patients showed significant increase in FXN expression by ~85%. Since inherited deficiency in FXN is the primary cause of FA, and DMF is demonstrated to increase FXN expression in humans, DMF could be considered for Friedreich's therapy.
Sunday, June 2, 2019
Efficient Electroporation of Neuronal Cells Using Synthetic Oligonucleotides: Identifying Duplex RNA and Antisense Oligonucleotide Activators of Human Frataxin Expression
Xiulong Shen, Sharon Beasley, Jennifer Putnam, Yanjie Li, Thahza Prakash, Frank Rigo, Marek Napierala, and David Corey. RNA rna.071290.119 Published in Advance May 31, 2019, doi:10.1261/rna.071290.119
We have previously shown that synthetic nucleic acids can activate FXN expression in human patient-derived fibroblast cells. We chose to further test these compounds in induced pluripotent stem cell-derived neuronal progenitor cells (iPSC-NPCs). Here we describe methods to deliver oligonucleotides and duplex RNAs into iPSC-NPC’s cells using electroporation. Activation of FXN expression is potent, easily reproducible, and potencies parallel those determined using patient-derived fibroblast cells. A duplex RNA and several antisense oligonucleotides with different combinations of 2’-methoxylethyl (2’-MOE), 2’-fluoro (2’-F), and constrained ethyl (cEt) were active, providing multiple starting points for further development and highlighting improved potency as an important goal for preclinical development. Our data support the conclusion that ASO-mediated activation of FXN is a feasible approach for treating FRDA and that electroporation is a robust method for introducing ASOs to modulate gene expressions in neuronal cells.
We have previously shown that synthetic nucleic acids can activate FXN expression in human patient-derived fibroblast cells. We chose to further test these compounds in induced pluripotent stem cell-derived neuronal progenitor cells (iPSC-NPCs). Here we describe methods to deliver oligonucleotides and duplex RNAs into iPSC-NPC’s cells using electroporation. Activation of FXN expression is potent, easily reproducible, and potencies parallel those determined using patient-derived fibroblast cells. A duplex RNA and several antisense oligonucleotides with different combinations of 2’-methoxylethyl (2’-MOE), 2’-fluoro (2’-F), and constrained ethyl (cEt) were active, providing multiple starting points for further development and highlighting improved potency as an important goal for preclinical development. Our data support the conclusion that ASO-mediated activation of FXN is a feasible approach for treating FRDA and that electroporation is a robust method for introducing ASOs to modulate gene expressions in neuronal cells.
Saturday, June 1, 2019
p53 Binds Preferentially to Non-B DNA Structures Formed by the Pyrimidine-Rich Strands of GAA·TTC Trinucleotide Repeats Associated with Friedreich’s Ataxia
Helma, R.; Bažantová, P.; Petr, M.; Adámik, M.; Renčiuk, D.; Tichý, V.; Pastuchová, A.; Soldánová, Z.; Pečinka, P.; Bowater, R.P.; Fojta, M.; Brázdová, M. . Molecules 2019, 24, 2078. doi: 10.3390/molecules24112078
In summary, we show that non-B DNA structures formed by TNR (TTC, GAA, CTG, CAG) and simple T-repeat are recognized by p53. Moreover, p53 prefers non-B DNA structures formed by the pyrimidine-rich strands of the investigated repetitive sequences and that the intact C-terminus is responsible for high p53 affinity to TNR non-B DNA structures. Further studies are needed to understand the precise function of p53 TNR non-B DNA recognition in relation to the development of Friedreich’s ataxia or other diseases coupled with TNR expansion.
In summary, we show that non-B DNA structures formed by TNR (TTC, GAA, CTG, CAG) and simple T-repeat are recognized by p53. Moreover, p53 prefers non-B DNA structures formed by the pyrimidine-rich strands of the investigated repetitive sequences and that the intact C-terminus is responsible for high p53 affinity to TNR non-B DNA structures. Further studies are needed to understand the precise function of p53 TNR non-B DNA recognition in relation to the development of Friedreich’s ataxia or other diseases coupled with TNR expansion.
Subscribe to:
Posts (Atom)
