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).
Wednesday, June 5, 2019
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.
Thursday, May 23, 2019
Chondrial Therapeutics, Inc., the Bala Cynwyd-based biopharmaceutical company, has raised $25.8 million to develop treatment for mitochondrial disorders.
THE INQUIRER, phillynews.com. Sam Wood, Updated: May 23, 2019
Chondrial Therapeutics, Inc., the Bala Cynwyd-based biopharmaceutical company, has raised $25.8 million to develop treatment for mitochondrial disorders.
Chondria’s FA therapy has the much-coveted orphan drug designation from the FDA. Chondrial will file an Investigational New Drug application in the next couple of months and go into trials “almost immediately”.
Chondrial Therapeutics, Inc., the Bala Cynwyd-based biopharmaceutical company, has raised $25.8 million to develop treatment for mitochondrial disorders.
Chondria’s FA therapy has the much-coveted orphan drug designation from the FDA. Chondrial will file an Investigational New Drug application in the next couple of months and go into trials “almost immediately”.
Saturday, May 18, 2019
Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism
Nicholas G. Fox, Xiaodi Yu, Xidong Feng, Henry J. Bailey, Alain Martelli, Joseph F. Nabhan, Claire Strain-Damerell, Christine Bulawa, Wyatt W. Yue & Seungil Han; Nature Communications volume 10, Article number: 2210 (2019). doi:10.1038/s41467-019-09989-y
The core machinery for de novo biosynthesis of iron-sulfur clusters (ISC), located in the mitochondria matrix, is a five-protein complex containing the cysteine desulfurase NFS1 that is activated by frataxin (FXN), scaffold protein ISCU, accessory protein ISD11, and acyl-carrier protein ACP. Deficiency in FXN leads to the loss-of-function neurodegenerative disorder Friedreich’s ataxia (FRDA). Here the 3.2 Å resolution cryo-electron microscopy structure of the FXN-bound active human complex, containing two copies of the NFS1-ISD11-ACP-ISCU-FXN hetero-pentamer, delineates the interactions of FXN with other component proteins of the complex. FXN binds at the interface of two NFS1 and one ISCU subunits, modifying the local environment of a bound zinc ion that would otherwise inhibit NFS1 activity in complexes without FXN. Our structure reveals how FXN facilitates ISC production through stabilizing key loop conformations of NFS1 and ISCU at the protein–protein interfaces, and suggests how FRDA clinical mutations affect complex formation and FXN activation.
The core machinery for de novo biosynthesis of iron-sulfur clusters (ISC), located in the mitochondria matrix, is a five-protein complex containing the cysteine desulfurase NFS1 that is activated by frataxin (FXN), scaffold protein ISCU, accessory protein ISD11, and acyl-carrier protein ACP. Deficiency in FXN leads to the loss-of-function neurodegenerative disorder Friedreich’s ataxia (FRDA). Here the 3.2 Å resolution cryo-electron microscopy structure of the FXN-bound active human complex, containing two copies of the NFS1-ISD11-ACP-ISCU-FXN hetero-pentamer, delineates the interactions of FXN with other component proteins of the complex. FXN binds at the interface of two NFS1 and one ISCU subunits, modifying the local environment of a bound zinc ion that would otherwise inhibit NFS1 activity in complexes without FXN. Our structure reveals how FXN facilitates ISC production through stabilizing key loop conformations of NFS1 and ISCU at the protein–protein interfaces, and suggests how FRDA clinical mutations affect complex formation and FXN activation.
Friday, May 17, 2019
Peripapillary retinal nerve fibre layer thickness in Friedreich’s ataxia: a biomarker for trials?
Gilbert J Thomas-Black Micheal H Parkinson Fion Bremner Paola Giunti; Brain, awz117, doi:10.1093/brain/awz117
The results from this study show that OCT measurements of RNFL thickness have the potential to become a robust and objective biomarker for future treatment trials in FRDA.
The results from this study show that OCT measurements of RNFL thickness have the potential to become a robust and objective biomarker for future treatment trials in FRDA.
Tuesday, May 14, 2019
Altered neocortical tactile but preserved auditory early change detection responses in Friedreich ataxia
Gilles Naeije, Vincent Wens, Mathieu Bourguignon, Serge Goldman, Massimo Pandolfo, Xavier De Tiège, Clinical Neurophysiology, 2019, ISSN 1388-2457, doi:10.1016/j.clinph.2019.05.003.
Evoked responses were detectable in all FRDA patients but one. In patients, TERs were delayed and reduced in amplitude, while AERs were only delayed. Only tactile MMN responses at the contralateral secondary somatosensory cortex were altered in FRDA patients. Maximal amplitudes of TERs, AERs and tactile MMN correlated with genotype, but did not correlate with clinical parameters.
In FRDA, the amplitude of tactile MMN responses at SII cortex are reduced and correlate with the genotype, while auditory MMN responses are not altered. Somatosensory pathways and tactile early change detection are selectively impaired in FRDA.
Evoked responses were detectable in all FRDA patients but one. In patients, TERs were delayed and reduced in amplitude, while AERs were only delayed. Only tactile MMN responses at the contralateral secondary somatosensory cortex were altered in FRDA patients. Maximal amplitudes of TERs, AERs and tactile MMN correlated with genotype, but did not correlate with clinical parameters.
In FRDA, the amplitude of tactile MMN responses at SII cortex are reduced and correlate with the genotype, while auditory MMN responses are not altered. Somatosensory pathways and tactile early change detection are selectively impaired in FRDA.
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