20-May-2020. PharmiWeb.com. Mataró, Barcelona, Spain and Charleroi, Belgium, May 12, 2020 – Minoryx Therapeutics, a company that specializes in the development of innovative treatments for orphan Central Nervous System (CNS) diseases, today announces the initiation of the registration-enabling Phase 2 NEXUS trial to evaluate the safety and efficacy of leriglitazone in pediatric patients with early-stage cerebral ALD (cALD), the acute form of X-linked adrenoleukodystrophy (X-ALD).
Leriglitazone has also completed enrolment in FRAMES, a one year double-blind, placebo-controlled Phase 2 study in patients with Friedreich’s Ataxia. Results from ADVANCE and FRAMES are expected by the end of 2020 and results from NEXUS are expected in 2021. Leriglitazone has obtained Orphan Drug Designation from the European Commission and the FDA in X-ALD and Friedreich’s Ataxia.
Thursday, May 21, 2020
Sunday, May 17, 2020
Non-Invasive Cerebellar Stimulation in Neurodegenerative Ataxia: A Literature Review
Benussi A, Pascual-Leone A, Borroni B.; International Journal of Molecular Sciences. 2020 Mar;21(6). DOI: 10.3390/ijms21061948.
In light of limited evidence-based pharmacologic and non-pharmacologic treatment options for patients with ataxia, several different non-invasive brain stimulation protocols have emerged, particularly employing repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) techniques. In this review, we summarize the most relevant rTMS and tDCS therapeutic trials and discuss their implications in the care of patients with degenerative ataxias.
In light of limited evidence-based pharmacologic and non-pharmacologic treatment options for patients with ataxia, several different non-invasive brain stimulation protocols have emerged, particularly employing repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) techniques. In this review, we summarize the most relevant rTMS and tDCS therapeutic trials and discuss their implications in the care of patients with degenerative ataxias.
Wednesday, May 13, 2020
J. Analysis of Putative Epigenetic Regulatory Elements in the FXN Genomic Locus
Fernández-Frías, I.; Pérez-Luz, S.; Díaz-Nido. Int. J. Mol. Sci. 2020, 21, 3410.
Friedreich´s ataxia (FRDA) is an autosomal recessive disease caused by an abnormally expanded Guanine-Adenine-Adenine (GAA) repeat sequence within the first intron of the frataxin gene (FXN). The molecular mechanisms associated with FRDA are still poorly understood and most studies on FXN gene regulation have been focused on the region around the minimal promoter and the region in which triplet expansion occurs. Nevertheless, since there could be more epigenetic changes involved in the reduced levels of FXN transcripts, the aim of this study was to obtain a more detailed view of the possible regulatory elements by analyzing data from ENCODE and Roadmap consortia databases. This bioinformatic analysis indicated new putative regulatory regions within the FXN genomic locus, including exons, introns, and upstream and downstream regions. Moreover, the region next to the end of intron 4 is of special interest, since the enhancer signals in FRDA-affected tissues are weak or absent in this region, whilst they are strong in the rest of the analyzed tissues. Therefore, these results suggest that there could be a direct relationship between the absence of enhancer sequences in this specific region and their predisposition to be affected in this pathology.
Friedreich´s ataxia (FRDA) is an autosomal recessive disease caused by an abnormally expanded Guanine-Adenine-Adenine (GAA) repeat sequence within the first intron of the frataxin gene (FXN). The molecular mechanisms associated with FRDA are still poorly understood and most studies on FXN gene regulation have been focused on the region around the minimal promoter and the region in which triplet expansion occurs. Nevertheless, since there could be more epigenetic changes involved in the reduced levels of FXN transcripts, the aim of this study was to obtain a more detailed view of the possible regulatory elements by analyzing data from ENCODE and Roadmap consortia databases. This bioinformatic analysis indicated new putative regulatory regions within the FXN genomic locus, including exons, introns, and upstream and downstream regions. Moreover, the region next to the end of intron 4 is of special interest, since the enhancer signals in FRDA-affected tissues are weak or absent in this region, whilst they are strong in the rest of the analyzed tissues. Therefore, these results suggest that there could be a direct relationship between the absence of enhancer sequences in this specific region and their predisposition to be affected in this pathology.
Sunday, May 10, 2020
Neurofilament light chain as a potential biomarker of disease status in Friedreich ataxia
Alexandra Clay, Kristin M. Obrochta, Russell K. Soon Jr, Christopher B. Russell & David R. Lynch; Neurol (2020). doi:10.1007/s00415-020-09868-3
Because NfL is elevated in patients, but decreases with age and disease progression, our results suggest that age is the critical determinant of NfL in FRDA (rather than clinical or genetic severity).
Because NfL is elevated in patients, but decreases with age and disease progression, our results suggest that age is the critical determinant of NfL in FRDA (rather than clinical or genetic severity).
Tuesday, May 5, 2020
Therapeutic potential of stem cells for treatment of neurodegenerative diseases
Ahmadian-Moghadam, H., Sadat-Shirazi, M. & Zarrindast, M.; Biotechnol Lett (2020). doi:10.1007/s10529-020-02886-1
The regenerative potential of stem cells drew the attention of researchers to cell-based therapy for treating neurodegenerative diseases. The clinical application of stem cells may help to substitute new cells and overcome the inability of the endogenous repairing system to repair the damaged brain. However, the clinical application induced pluripotent stem cells are restricted due to the risk of tumor formation by residual undifferentiated upon transplantation. In this focused review, we briefly discussed different stem cells currently being studied for therapeutic development. Moreover, we present supporting evidence for the utilization of stem cell therapy for the treatment of neurodegenerative diseases.
The regenerative potential of stem cells drew the attention of researchers to cell-based therapy for treating neurodegenerative diseases. The clinical application of stem cells may help to substitute new cells and overcome the inability of the endogenous repairing system to repair the damaged brain. However, the clinical application induced pluripotent stem cells are restricted due to the risk of tumor formation by residual undifferentiated upon transplantation. In this focused review, we briefly discussed different stem cells currently being studied for therapeutic development. Moreover, we present supporting evidence for the utilization of stem cell therapy for the treatment of neurodegenerative diseases.
Monday, May 4, 2020
CRISPR/Cas9 gene editing of hematopoietic stem cells from patients with Friedreich’s ataxia
Celine J. Rocca, Joseph N. Rainaldi, Jay Sharma, Yanmeng Shi, Joseph H. Haquang, Jens Luebeck, Prashant Mali, Stephanie Cherqui, Molecular Therapy - Methods & Clinical Development, 2020, doi:10.1016/j.omtm.2020.04.018.
Here, we report the first step towards an autologous HSPC transplantation using the CRISPR/Cas9 system for FRDA. We first identified a pair of crRNAs that efficiently removes the GAA expansions in human FRDA lymphoblasts restoring non-pathologic level of frataxin expression and normalizing mitochondrial activity. We also optimized the gene editing approach in HSPCs isolated from healthy and FRDA patients’ peripheral blood, and demonstrated normal hematopoiesis of gene-edited cells in vitro and in vivo. The procedure did not induce cellular toxic effect or major off-target events, but a p53-mediated cell proliferation delay was observed in the gene-edited cells. This study provides the foundation for the clinical translation of autologous transplantation of gene-corrected HSPCs for FRDA.
Here, we report the first step towards an autologous HSPC transplantation using the CRISPR/Cas9 system for FRDA. We first identified a pair of crRNAs that efficiently removes the GAA expansions in human FRDA lymphoblasts restoring non-pathologic level of frataxin expression and normalizing mitochondrial activity. We also optimized the gene editing approach in HSPCs isolated from healthy and FRDA patients’ peripheral blood, and demonstrated normal hematopoiesis of gene-edited cells in vitro and in vivo. The procedure did not induce cellular toxic effect or major off-target events, but a p53-mediated cell proliferation delay was observed in the gene-edited cells. This study provides the foundation for the clinical translation of autologous transplantation of gene-corrected HSPCs for FRDA.
Friday, May 1, 2020
A Phase 1 Study to Assess the Safety, Tolerability, Pharmacokinetics, and Effects on Biomarkers of MIN-102 (Leriglitazone)
Uwe Meya, Guillem Pina, Silvia Pascual, Marc Cerrada-Gimenez, Pilar Pizcueta, Marc Martinell, David Eckland, Jeroen v.d. Wetering de Rooij
Neurology Apr 2020, 94 (15 Supplement)
Evaluation of the pharmacokinetic parameters of leriglitazone in plasma and urine after single and multiple oral administration in healthy male volunteers. Evaluation of pro-inflammatory biomarkers in plasma and CSF after oral administration of leriglitazone in healthy male volunteers.
Neurology Apr 2020, 94 (15 Supplement)
Evaluation of the pharmacokinetic parameters of leriglitazone in plasma and urine after single and multiple oral administration in healthy male volunteers. Evaluation of pro-inflammatory biomarkers in plasma and CSF after oral administration of leriglitazone in healthy male volunteers.
Thursday, April 30, 2020
MIN102 (Leriglitazone), a Brain Penetrant PPAR Gamma Agonist for the Treatment of Friedreich’s Ataxia (4147)
Sonia Poli, Laura Rodríguez-Pascau, Elena Britti, Joaquim Ros, Pilar González-Cab, David Lynch, Marc Martinell, Pilar Pizcueta; Neurology Apr 2020, 94 (15 Supplement) 4147;
The preclinical results support the investigation of leriglitazone for the treatment of FRDA. Leriglitazone is currently in clinical phase 2/3 for the treatment of AMN, in phase 2 for cALD and in phase 2 for Friedreich’s Ataxia.
The preclinical results support the investigation of leriglitazone for the treatment of FRDA. Leriglitazone is currently in clinical phase 2/3 for the treatment of AMN, in phase 2 for cALD and in phase 2 for Friedreich’s Ataxia.
Monday, April 27, 2020
Neurologic outcomes in Friedreich ataxia
Massimo Pandolfo, Neurol Genet Jun 2020, 6 (3) e415; DOI: 10.1212/NXG.0000000000000415
The SARA is a sensitive outcome measure in ambulatory patients with FRDA and has an excellent correlation with functional capabilities. Ambulatory patients with onset before age 8 years showed the fastest measurable worsening. Loss of ambulation in high-risk patients is a disease milestone that should be considered as an end point in clinical trials.
The SARA is a sensitive outcome measure in ambulatory patients with FRDA and has an excellent correlation with functional capabilities. Ambulatory patients with onset before age 8 years showed the fastest measurable worsening. Loss of ambulation in high-risk patients is a disease milestone that should be considered as an end point in clinical trials.
Thursday, April 23, 2020
Making iron-sulfur cluster: structure, regulation and evolution of the bacterial ISC system
Corentin Baussier, Soufyan Fakroun, Corinne Aubert, Sarah Dubrac, Pierre Mandin, Béatrice Py, Frédéric Barras, Advances in Microbial Physiology, Academic Press, 2020, doi:10.1016/bs.ampbs.2020.01.001.
Iron sulfur (Fe-S) clusters rank among the most ancient and conserved prosthetic groups. Fe-S clusters containing proteins are present in most, if not all, organisms. Fe-S clusters containing proteins are involved in a wide range of cellular processes, from gene regulation to central metabolism, via gene expression, RNA modification or bioenergetics. Fe-S clusters are built by biogenesis machineries conserved throughout both prokaryotes and eukaryotes. We focus mostly on bacterial ISC machinery, but not exclusively, as we refer to eukaryotic ISC system when it brings significant complementary information. Besides covering the structural and regulatory aspects of Fe-S biogenesis, this review aims to highlight Fe-S biogenesis facets remaining matters of discussion, such as the role of frataxin, or the link between fatty acid metabolism and Fe-S homeostasis. Last, we discuss recent advances on strategies used by different species to make and use Fe-S clusters in changing redox environmental conditions.
Iron sulfur (Fe-S) clusters rank among the most ancient and conserved prosthetic groups. Fe-S clusters containing proteins are present in most, if not all, organisms. Fe-S clusters containing proteins are involved in a wide range of cellular processes, from gene regulation to central metabolism, via gene expression, RNA modification or bioenergetics. Fe-S clusters are built by biogenesis machineries conserved throughout both prokaryotes and eukaryotes. We focus mostly on bacterial ISC machinery, but not exclusively, as we refer to eukaryotic ISC system when it brings significant complementary information. Besides covering the structural and regulatory aspects of Fe-S biogenesis, this review aims to highlight Fe-S biogenesis facets remaining matters of discussion, such as the role of frataxin, or the link between fatty acid metabolism and Fe-S homeostasis. Last, we discuss recent advances on strategies used by different species to make and use Fe-S clusters in changing redox environmental conditions.
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