BALA CYNWYD, Pa., July 20, 2020 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Nasdaq:LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, today announced that patients have been dosed in the third cohort of a Phase 1 clinical trial to evaluate the safety and tolerability of single ascending doses (SAD) of CTI-1601 for the treatment of Friedreich’s ataxia (FA). The trial was previously delayed due to the impact of the COVID-19 pandemic. CTI-1601 is a recombinant fusion protein intended to deliver human frataxin into the mitochondria of patients with FA who are unable to produce enough of this essential protein.
“We’re pleased that our Phase 1 clinical trial has resumed and we can continue to move forward with our lead product candidate, CTI-1601, which has the potential to become the first frataxin replacement therapy for patients with FA,” said Carole Ben-Maimon, MD, President and Chief Executive Officer of Larimar Therapeutics. “Our highest priority remains the health of our employees and patients especially given the COVID-19 pandemic. We have thoughtfully re-engaged with our clinical site to mitigate the safety risks.”
Additional information on the trial can be found on www.clinicaltrials.gov using the identifier NCT04176991.
Tuesday, July 21, 2020
Sunday, July 19, 2020
Safety and Efficacy of (+)-Epicatechin in Subjects with Friedreich's Ataxia: A Phase II, Open-Label, Prospective Study
Qureshi, M. Y., Patterson, M. C., Clark, V., Johnson, J. N., Moutvic, M. A., Driscoll, S. W., Kemppainen, J. L., Huston, J., 3rd, Anderson, J. R., Badley, A. D., Tebben, P. J., Wackel, P., Oglesbee, D., Glockner, J., Schreiner, G., Dugar, S., Touchette, J. C., & Gavrilova, R. H. (2020). Journal of inherited metabolic disease, 10.1002/jimd.12285. Advance online publication. doi:10.1002/jimd.12285
(+)-EPI was well tolerated over 24 weeks at up to 150 mg/day. Improvement was observed in cardiac structure and function in subset of subjects with FRDA without statistically significant improvement in primary neurological outcomes.
(+)-EPI was well tolerated over 24 weeks at up to 150 mg/day. Improvement was observed in cardiac structure and function in subset of subjects with FRDA without statistically significant improvement in primary neurological outcomes.
Sunday, July 12, 2020
Stress-induced Mouse Model of the Cardiac Manifestations of Friedreich's Ataxia Corrected by AAV-mediated Gene Therapy
Ms. Christiana Salami, Ms. Katie Jackson, Ms. Clarisse L. Jose, Mr. Laith Alyass, Mr. Georges-Ibrahim Cisse, Dr. Bishnu P De, Dr. Katie Stiles, Dr. Maria J. Chiuchiolo, Dr. Dolan Sondhi, Dr. Ronald G Crystal, and Dr. Stephen M. Kaminsky. Human Gene Therapy. Ahead of print doi:10.1089/hum.2019.363
The study was designed to create a mouse model for early FA disease relevant to the time for which a gene therapy would likely be most effective. To generate a cardiac-specific mouse model of FA cardiomyopathy similar to the human disease, we used a cardiac promoter (αMyhc) driving Cre-recombinase cardiac-specific excision of FXN exon 4 to generate a mild cardiac-specific FA model that is normal at rest but exhibits the cardiac phenotype with stress.
A one-time intravenous administration of 1011 genome copies of AAVrh.10hFXN, an adeno-associated virus serotype rh10 gene transfer vector expressing human FXN, corrected the stress-induced ejection fraction and fractional shortening phenotypes. Treated αMyhc mice exhibited exercise performance on a treadmill indistinguishable from littermate controls. These αMyhc mice provide an ideal model to study long-term cardiac complications due to FA and AAV-mediated gene therapy correction of stress-induced cardiac phenotypes typical of human FA.
The study was designed to create a mouse model for early FA disease relevant to the time for which a gene therapy would likely be most effective. To generate a cardiac-specific mouse model of FA cardiomyopathy similar to the human disease, we used a cardiac promoter (αMyhc) driving Cre-recombinase cardiac-specific excision of FXN exon 4 to generate a mild cardiac-specific FA model that is normal at rest but exhibits the cardiac phenotype with stress.
A one-time intravenous administration of 1011 genome copies of AAVrh.10hFXN, an adeno-associated virus serotype rh10 gene transfer vector expressing human FXN, corrected the stress-induced ejection fraction and fractional shortening phenotypes. Treated αMyhc mice exhibited exercise performance on a treadmill indistinguishable from littermate controls. These αMyhc mice provide an ideal model to study long-term cardiac complications due to FA and AAV-mediated gene therapy correction of stress-induced cardiac phenotypes typical of human FA.
Thursday, July 9, 2020
Compound heterozygosity for an expanded (GAA) and a (GAAGGA) repeat at FXN locus: from a diagnostic pitfall to potential clues to the pathogenesis of Friedreich ataxia
Massimo Santoro, Alessia Perna, Piergiorgio La Rosa, Sara Petrillo, Fiorella Piemonte, Salvatore Rossi, Vittorio Riso, Tommaso Filippo Nicoletti, Anna Modoni, Maria Grazia Pomponi, Pietro Chiurazzi & Gabriella Silvestri; Neurogenetics (2020). doi:10.1007/s10048-020-00620-7
This report highlights a rare but possible pitfall in FRDA molecular diagnosis, emphasizing the need of further analysis in case of discrepancy between clinical and molecular data.
This report highlights a rare but possible pitfall in FRDA molecular diagnosis, emphasizing the need of further analysis in case of discrepancy between clinical and molecular data.
Saturday, July 4, 2020
Analysis of Postural Control in Sitting by Pressure Mapping in Patients With Multiple Sclerosis, Spinal Cord Injury and Friedreich's Ataxia
María Mercedes Reguera-García, Raquel Leirós-Rodríguez, Lorena Álvarez-Barrio, Beatriz Alonso-Cortés Fradejas; Preprint from Research Square, 05 Jun 2020 DOI: 10.21203/rs.3.rs-32856/v1
The tools available for the postural control assessment in patients with neurological diseases lack reliability and sensitivity to small changes in patient functionality. The appearance of pressure mapping has allowed quantitative evaluation of postural control in sitting. This study was carried out todetermine the evaluations in pressure mapping and verifying whether they are different between the three sample groups (multiple sclerosis, spinal cord injury and Friedreich's ataxia), and to determine whether the pressure mapping is more sensitive than functional tests.
The tools available for the postural control assessment in patients with neurological diseases lack reliability and sensitivity to small changes in patient functionality. The appearance of pressure mapping has allowed quantitative evaluation of postural control in sitting. This study was carried out todetermine the evaluations in pressure mapping and verifying whether they are different between the three sample groups (multiple sclerosis, spinal cord injury and Friedreich's ataxia), and to determine whether the pressure mapping is more sensitive than functional tests.
Thursday, July 2, 2020
Medical and Paramedical Care of Patients With Cerebellar Ataxia During the COVID-19 Outbreak: Seven Practical Recommendations of the COVID 19 Cerebellum Task Force.
Manto M, Dupre N, Hadjivassiliou M, Louis ED, Mitoma H, Molinari M, Shaikh AG, Soong B-W, Strupp M, Van Overwalle F and Schmahmann JD (2020). Front. Neurol. 11:516. doi: 10.3389/fneur.2020.00516
None of us has ever personally encountered such a dire situation as is posed by this pandemic. This set of recommendations offered by the international panel of ataxia experts is based on our collective clinical experience and review of the rapidly expanding clinical and basic science literature. We expect that the results of clinical trials and larger studies of the pandemic in all its manifestations will enable us to provide more substantive and evidence-based guidelines for neurologists, including ataxiologists, in the future.
None of us has ever personally encountered such a dire situation as is posed by this pandemic. This set of recommendations offered by the international panel of ataxia experts is based on our collective clinical experience and review of the rapidly expanding clinical and basic science literature. We expect that the results of clinical trials and larger studies of the pandemic in all its manifestations will enable us to provide more substantive and evidence-based guidelines for neurologists, including ataxiologists, in the future.
Wednesday, July 1, 2020
Feasibility and Acceptability of Lee Silverman Voice Treatment in Progressive Ataxias
Lowit, A., Egan, A. & Hadjivassiliou, M.; Cerebellum (2020). doi:10.1007/s12311-020-01153-3
LSVT LOUD® focuses on the production of healthy vocal loudness whilst also improving breath support, vocal quality, loudness and articulation in participating patients. This study aimed to investigate whether Lee Silverman Voice Treatment (LSVT LOUD®) can improve communication effectiveness in these patients. We performed a rater-blinded, single-arm study investigating LSVT LOUD® treatment in a population of patients with progressive ataxia including Friedreich’s ataxia (n = 18), spinocerebellar ataxia type 6 (n = 1), idiopathic cerebellar ataxia (n = 1), and spastic paraplegia 7 (n = 1).
This is the largest treatment study for people with progressive ataxia published to date. It provides an indication that LSVT LOUD® can have a positive impact on communication in this patient group and could form the basis for larger-scale trials.
LSVT LOUD® focuses on the production of healthy vocal loudness whilst also improving breath support, vocal quality, loudness and articulation in participating patients. This study aimed to investigate whether Lee Silverman Voice Treatment (LSVT LOUD®) can improve communication effectiveness in these patients. We performed a rater-blinded, single-arm study investigating LSVT LOUD® treatment in a population of patients with progressive ataxia including Friedreich’s ataxia (n = 18), spinocerebellar ataxia type 6 (n = 1), idiopathic cerebellar ataxia (n = 1), and spastic paraplegia 7 (n = 1).
This is the largest treatment study for people with progressive ataxia published to date. It provides an indication that LSVT LOUD® can have a positive impact on communication in this patient group and could form the basis for larger-scale trials.
Friday, June 26, 2020
Mitochondrial damage and senescence phenotype of cells derived from a novel frataxin G127V point mutation mouse model of Friedreich's ataxia
Daniel Fil, Balu K. Chacko, Robbie Conley, Xiaosen Ouyang, Jianhua Zhang, Victor M. Darley-Usmar, Aamir R. Zuberi, Cathleen M. Lutz, Marek Napierala, Jill S. Napierala; Disease Models & Mechanisms 2020 : dmm.045229 doi: 10.1242/dmm.045229 Published 25 June 2020
We report generation of the first mouse model harboring a Fxn point mutation. Changing the evolutionarily conserved glycine 127 in mouse Fxn to valine results in a failure to thrive phenotype in homozygous animals and a substantially reduced number of offspring. Like G130V in FRDA, the G127V mutation results in a dramatic decrease of Fxn protein without affecting transcript synthesis or splicing. FxnG127V mouse embryonic fibroblasts exhibit significantly reduced proliferation and increased cell senescence. These defects are evident in early passage cells and are exacerbated at later passages. Furthermore, increased frequency of mitochondrial DNA (mtDNA) lesions and fragmentation are accompanied by marked amplification of mtDNA in FxnG127V cells. Bioenergetics analyses demonstrate higher sensitivity and reduced cellular respiration of FxnG127V cells upon alteration of fatty acid availability. Importantly, substitution of FxnWT with FxnG127V is compatible with life and cellular proliferation defects can be rescued by mitigation of oxidative stress via hypoxia or induction of the NRF2 pathway. We propose FxnG127V cells as a simple and robust model for testing therapeutic approaches for FRDA.
We report generation of the first mouse model harboring a Fxn point mutation. Changing the evolutionarily conserved glycine 127 in mouse Fxn to valine results in a failure to thrive phenotype in homozygous animals and a substantially reduced number of offspring. Like G130V in FRDA, the G127V mutation results in a dramatic decrease of Fxn protein without affecting transcript synthesis or splicing. FxnG127V mouse embryonic fibroblasts exhibit significantly reduced proliferation and increased cell senescence. These defects are evident in early passage cells and are exacerbated at later passages. Furthermore, increased frequency of mitochondrial DNA (mtDNA) lesions and fragmentation are accompanied by marked amplification of mtDNA in FxnG127V cells. Bioenergetics analyses demonstrate higher sensitivity and reduced cellular respiration of FxnG127V cells upon alteration of fatty acid availability. Importantly, substitution of FxnWT with FxnG127V is compatible with life and cellular proliferation defects can be rescued by mitigation of oxidative stress via hypoxia or induction of the NRF2 pathway. We propose FxnG127V cells as a simple and robust model for testing therapeutic approaches for FRDA.
Tuesday, June 23, 2020
DNA Hypermethylation and Unstable Repeat Diseases: A Paradigm of Transcriptional Silencing to Decipher the Basis of Pathogenic Mechanisms
Poeta, Loredana; Drongitis, Denise; Verrillo, Lucia; Miano , Maria Giuseppina; Genes 11, no. 6: 684. doi:10.3390/genes11060684
We report on a brief description of advanced strategies in DNA methylation profiling for the identification of unstable Guanine-Cytosine (GC)-rich regions and on promising examples of molecular targeted therapies for Fragile X disease (FXS) and Friedrich ataxia (FRDA) that could pave the way for the application of this technique in other hypermethylated expansion disorders.
We report on a brief description of advanced strategies in DNA methylation profiling for the identification of unstable Guanine-Cytosine (GC)-rich regions and on promising examples of molecular targeted therapies for Fragile X disease (FXS) and Friedrich ataxia (FRDA) that could pave the way for the application of this technique in other hypermethylated expansion disorders.
Thursday, June 18, 2020
NRF2 Regulation Processes as a Source of Potential Drug Targets against Neurodegenerative Diseases
Cores, Á.; Piquero, M.; Villacampa, M.; León, R.; Menéndez, J.C; Biomolecules 2020, 10, 904. doi:10.3390/biom10060904
NRF2 acts by controlling gene expression, being the master regulator of the Phase II antioxidant response, and also being key to the control of neuroinflammation. NRF2 activity is regulated at several levels, including protein degradation by the proteasome, transcription, and post-transcription. The purpose of this review is to offer a concise and critical overview of the main mechanisms of NRF2 regulation and their actual or potential use as targets for the treatment of neurodegenerative diseases.
NRF2 acts by controlling gene expression, being the master regulator of the Phase II antioxidant response, and also being key to the control of neuroinflammation. NRF2 activity is regulated at several levels, including protein degradation by the proteasome, transcription, and post-transcription. The purpose of this review is to offer a concise and critical overview of the main mechanisms of NRF2 regulation and their actual or potential use as targets for the treatment of neurodegenerative diseases.
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