Legrand, L.; Maupain, C.; Monin, M.-L.; Ewenczyk, C.; Isnard, R.; Alkouri, R.; Durr, A.; Pousset, F.; J. Clin. Med. 2020, 9, 1630. doi:10.3390/jcm9061630
Conclusion: hsTnT was increased in 1/3 of the adult FA and associated with increased septal wall thickness. Increased NT-proBNP remained a marker of increased left ventricular filling pressure. This could be used to identify patients that should undergo a closer cardiac surveillance.
Friday, May 29, 2020
Friday, May 22, 2020
Efficacy and Safety of CSF- Delivered AVXS-401 in Mice and NonHuman Primates for the Treatment of Friedreich’s Ataxia
Martin Fugere, Rajeev Sivasankaran, Susan McQuown, Chang Choi, Katrina Salvador, Shirley Phillips, Yin Gu, Binh Chu, Janet Do, Tsun-Kai Chang, Katherine Nguyen, Yanchi Li, Stephanie Solano, Natalia Teider, Colin Fennelly, Ricardo Dolmetsch, Monica Bennett, Kevin Foust, Page Bouchard; AveXis Research and Development, San Diego, CA, Novartis Institutes for Biomedical Research, Cambridge, MA
For clinical translation, we developed AVXS-401, a self-complementary adenoassociated virus (AAV9) based gene replacement therapy to provide sustained expression of FXN in key tissues relevant to FA. Toxicity studies in wildtype mice proved AVXS-401 is safe and well-tolerated. Dose ranging efficacy studies following a one-time, pre-symptomatic intracerebroventricular (ICV) administration of AVXS-401 in conditional FXN-deficient mice in the CNS (Pvalb) demonstrates amelioration of behavioral phenotypes, rescue of Purkinje neurons and cerebellar gliosis at low doses. ICV delivery of AVXS-401 in cardiac mutants (MCK) results in full recovery of cardiac functions as measured by magnetic resonance imaging (MRI), prevention of histopathological evidence of cardiomyopathy and >300% increase in median survival at efficacious doses.
Scale up of therapeutic doses to non-human primates (NHP) showed that AVXS-401 is safe and well tolerated with no aberrant behavior, clinical or anatomical pathology attributable to frataxin expression. Importantly, AVXS-401 provides durable mRNA transcription in the CNS and heart of NHP at 6 months postinjection with frataxin expression detectable above endogenous levels. Dose escalation studies by intrathecal (IT) administration in NHP show a dose correlation between mice and NHP by ddPCR quantification of vector genomes. Together these pre-clinical data show that AVXS-401 is suitable for first-inhuman studies.
For clinical translation, we developed AVXS-401, a self-complementary adenoassociated virus (AAV9) based gene replacement therapy to provide sustained expression of FXN in key tissues relevant to FA. Toxicity studies in wildtype mice proved AVXS-401 is safe and well-tolerated. Dose ranging efficacy studies following a one-time, pre-symptomatic intracerebroventricular (ICV) administration of AVXS-401 in conditional FXN-deficient mice in the CNS (Pvalb) demonstrates amelioration of behavioral phenotypes, rescue of Purkinje neurons and cerebellar gliosis at low doses. ICV delivery of AVXS-401 in cardiac mutants (MCK) results in full recovery of cardiac functions as measured by magnetic resonance imaging (MRI), prevention of histopathological evidence of cardiomyopathy and >300% increase in median survival at efficacious doses.
Scale up of therapeutic doses to non-human primates (NHP) showed that AVXS-401 is safe and well tolerated with no aberrant behavior, clinical or anatomical pathology attributable to frataxin expression. Importantly, AVXS-401 provides durable mRNA transcription in the CNS and heart of NHP at 6 months postinjection with frataxin expression detectable above endogenous levels. Dose escalation studies by intrathecal (IT) administration in NHP show a dose correlation between mice and NHP by ddPCR quantification of vector genomes. Together these pre-clinical data show that AVXS-401 is suitable for first-inhuman studies.
Thursday, May 21, 2020
PTC announced delays in its gene therapy program for Friedreich’s ataxia
MAY 19, 2020. PTC announced delays in its gene therapy program for Friedreich’s ataxia and in the opening of a manufacturing facility in New Jersey, which is now expected to begin producing clinical material early next year.
Minoryx Therapeutics doses first patient with leriglitazone in registration-enabling cALD NEXUS trial
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.
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.
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.
Subscribe to:
Posts (Atom)
