Sylvain Gervason, Djabir Larkem, Amir Ben Mansour, Thomas Botzanowski, Christina S. Müller, Ludovic Pecqueur, Gwenaelle Le Pavec, Agnès Delaunay-Moisan, Omar Brun, Jordi Agramunt, Anna Grandas, Marc Fontecave, Volker Schünemann, Sarah Cianférani, Christina Sizun, Michel B. Tolédano & Benoit D’Autréaux;Nature Communicationsvolume 10, Article number: 3566 (2019), doi:10.1038/s41467-019-11470-9
Here, we report the breakdown of this process, made possible by removing a zinc ion in ISCU that hinders iron insertion and promotes non-physiological Fe-S cluster synthesis from free sulfide in vitro. By binding zinc-free ISCU, iron drives persulfide uptake from NFS1 and allows persulfide reduction into sulfide by FDX2, thereby coordinating sulfide production with its availability to generate Fe-S clusters. FXN stimulates the whole process by accelerating persulfide transfer. We propose that this reconstitution recapitulates physiological conditions which provides a model for Fe-S cluster biosynthesis, clarifies the roles of FDX2 and FXN and may help develop Friedreich’s ataxia therapies.
Friday, August 9, 2019
Thursday, August 8, 2019
A Collaborative-Filtering-Based Data Collection Strategy for Friedreich’s Ataxia
Wenbin Yue, Zidong Wang, Bo Tian, Annette Payne, Xiaohui Liu. Cogn Comput (2019). doi:10.1007/s12559-019-09674-8
We propose a novel data collection strategy for the FRDA baseline data by using the collaborative filtering (CF) approaches. This strategy is motivated by the popularity of the nowadays “Recommendation System” whose central idea is based on the fact that similar patients have similar symptoms on each test item. By doing so, instead of having no data at all, the FRDA researchers would be provided with certain predicted baseline data on patients who cannot attend the assessments for physical/psychological reasons, thereby helping with the data analysis from the researchers’ perspective. It is shown that the CF approaches are capable of predicting baseline data based on the similarity in test items of the patients, where the prediction accuracy is evaluated based on three rating scales selected from the EFACTS database. Experimental results demonstrate the validity and efficiency of the proposed strategy.
We propose a novel data collection strategy for the FRDA baseline data by using the collaborative filtering (CF) approaches. This strategy is motivated by the popularity of the nowadays “Recommendation System” whose central idea is based on the fact that similar patients have similar symptoms on each test item. By doing so, instead of having no data at all, the FRDA researchers would be provided with certain predicted baseline data on patients who cannot attend the assessments for physical/psychological reasons, thereby helping with the data analysis from the researchers’ perspective. It is shown that the CF approaches are capable of predicting baseline data based on the similarity in test items of the patients, where the prediction accuracy is evaluated based on three rating scales selected from the EFACTS database. Experimental results demonstrate the validity and efficiency of the proposed strategy.
Wednesday, August 7, 2019
Reata gets another shot in Friedreich’s ataxia
EvaluatePharma. August 06, 2019.
Pharmaceuticals will soon find out if its decision to persevere with omaveloxolone despite an earlier failure has paid off.
The signs are not auspicious: the first part of the same study did not show a benefit with omaveloxolone on the primary endpoint, peak work during maximal exercise testing, or its secondary endpoint, change versus placebo on the modified Friedreich’s ataxia rating scale (mFARS), when it reported two years ago (Friedreich's failure highlights thinning pipeline, 2 June 2017).
Despite this, Reata claimed that the data were positive, and Vinny Jindal, the group’s vice-president of strategy, told Vantage: “I wouldn’t classify part one of Moxie as a failure.” He added that the study had found a “meaningful” effect on patients, as measured by mFARS, a 100-point scale on which a higher score represents more severe disease.
Mr Jindal pointed to a 2.3-point placebo-corrected reduction on mFARS after 12 weeks' treatment with omaveloxolone 160mg, the best-performing dose in part one. This missed statistical significance with a p value of 0.06.
Nevertheless, Mr Jindal maintained: “Patients typically progress 1-2 points per year, so that improvement [could save patients] more than a year of progression.”
Pharmaceuticals will soon find out if its decision to persevere with omaveloxolone despite an earlier failure has paid off.
The signs are not auspicious: the first part of the same study did not show a benefit with omaveloxolone on the primary endpoint, peak work during maximal exercise testing, or its secondary endpoint, change versus placebo on the modified Friedreich’s ataxia rating scale (mFARS), when it reported two years ago (Friedreich's failure highlights thinning pipeline, 2 June 2017).
Despite this, Reata claimed that the data were positive, and Vinny Jindal, the group’s vice-president of strategy, told Vantage: “I wouldn’t classify part one of Moxie as a failure.” He added that the study had found a “meaningful” effect on patients, as measured by mFARS, a 100-point scale on which a higher score represents more severe disease.
Mr Jindal pointed to a 2.3-point placebo-corrected reduction on mFARS after 12 weeks' treatment with omaveloxolone 160mg, the best-performing dose in part one. This missed statistical significance with a p value of 0.06.
Nevertheless, Mr Jindal maintained: “Patients typically progress 1-2 points per year, so that improvement [could save patients] more than a year of progression.”
Monday, August 5, 2019
Pharmaceutical compounding of orphan active ingredients in Belgium: how community and hospital pharmacists can address the needs of patients with rare diseases
V. Vanhoorne, E. Peeters, I. Van Tongelen, K. Boussery, E. Wynendaele, B. De Spiegeleer, J. P. Remon & C. Vervaet ; Orphanet Journal of Rare Diseasesvolume 14, Article number: 186 (2019) DOI 10.1186/s13023-019-1154-x
Pharmaceutical compounding of orphan active ingredients can offer cost-effective treatment to patients when no other drug product is available for a rare disease or during periods of drug product shortages. Additionally, it allows customized therapy for patients with rare diseases. However, standardized compounding formulas and procedures, and monographs are required to ensure the patients’ safety.
Compounded preparations of OAIs can improve patients’ access to treatment for rare diseases. However, they should be prepared in accordance to standardized formulas and compounding procedures and the quality of the OAI should be demonstrated by a certificate of analysis according to a specific monograph. In current study, such standardized formulas and compounding procedures were developed for seven OAIs to treat patients with rare diseases when no other treatment is available. More efforts are needed to develop standardized formulas and compounding procedures for additional OAIs whose clinical efficacy is well-known but are not available yet to patients due to lack of interest from the pharmaceutical industry to apply for market authorization as OMP. Additionally, a legal framework at EU level is required to enable the potential of pharmaceutical compounding for OAIs.
Pharmaceutical compounding of orphan active ingredients can offer cost-effective treatment to patients when no other drug product is available for a rare disease or during periods of drug product shortages. Additionally, it allows customized therapy for patients with rare diseases. However, standardized compounding formulas and procedures, and monographs are required to ensure the patients’ safety.
Compounded preparations of OAIs can improve patients’ access to treatment for rare diseases. However, they should be prepared in accordance to standardized formulas and compounding procedures and the quality of the OAI should be demonstrated by a certificate of analysis according to a specific monograph. In current study, such standardized formulas and compounding procedures were developed for seven OAIs to treat patients with rare diseases when no other treatment is available. More efforts are needed to develop standardized formulas and compounding procedures for additional OAIs whose clinical efficacy is well-known but are not available yet to patients due to lack of interest from the pharmaceutical industry to apply for market authorization as OMP. Additionally, a legal framework at EU level is required to enable the potential of pharmaceutical compounding for OAIs.
Sunday, August 4, 2019
Exploring iron-binding to human frataxin and to selected Friedreich ataxia mutants by means of NMR and EPR spectroscopies
Massimo Bellanda, Lorenzo Maso, Davide Doni, Marco Bortolus, Edith De Rosa, Federica Lunardi, Arianna Alfonsi, Martín Ezequiel Noguera, Maria Georgina Herrera, Javier Santos, Donatella Carbonera, Paola Costantini; Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 2019, doi:10.1016/j.bbapap.2019.07.007.
n this work we combined different advanced spectroscopic analyses to explore the iron-binding properties of human frataxin, as isolated and at the FeS clusters assembly machinery. For the first time we used EPR spectroscopy to address this key issue providing clear evidence of the formation of a complex with a low symmetry coordination of the metal ion. By 2D NMR, we confirmed that iron can be bound in both oxidation states, a controversial issue, and, in addition, we were able to point out a transient interaction of frataxin with a N-terminal 6his-tagged variant of ISCU, the scaffold protein of the FeS clusters assembly machinery. To obtain insights on structure/function relationships relevant to understand the disease molecular mechanism(s), we extended our studies to four clinical frataxin mutants. All variants showed a moderate to strong impairment in their ability to activate the FeS cluster assembly machinery in vitro, while keeping the same iron-binding features of the wild type protein. This supports the multifunctional nature of frataxin and the complex biochemical consequences of its mutations.
Exploring iron-binding to human frataxin and to selected Friedreich ataxia mutants by means of NMR and EPR spectroscopies
n this work we combined different advanced spectroscopic analyses to explore the iron-binding properties of human frataxin, as isolated and at the FeS clusters assembly machinery. For the first time we used EPR spectroscopy to address this key issue providing clear evidence of the formation of a complex with a low symmetry coordination of the metal ion. By 2D NMR, we confirmed that iron can be bound in both oxidation states, a controversial issue, and, in addition, we were able to point out a transient interaction of frataxin with a N-terminal 6his-tagged variant of ISCU, the scaffold protein of the FeS clusters assembly machinery. To obtain insights on structure/function relationships relevant to understand the disease molecular mechanism(s), we extended our studies to four clinical frataxin mutants. All variants showed a moderate to strong impairment in their ability to activate the FeS cluster assembly machinery in vitro, while keeping the same iron-binding features of the wild type protein. This supports the multifunctional nature of frataxin and the complex biochemical consequences of its mutations.
Exploring iron-binding to human frataxin and to selected Friedreich ataxia mutants by means of NMR and EPR spectroscopies
Saturday, August 3, 2019
BioMarin announced plans to discontinue preclinical studies in the BMN290 programme for Friedreich’s Ataxia
August 2019. BioMarin’s BMN 290 Programme: An Update for the Friedreich’s Ataxia Community On August 1, 2019 BioMarin announced plans to discontinue preclinical studies in the BMN290 programme for Friedreich’s Ataxia. BMN 290 is a selective chromatin modulationtherapy that has been under investigation as an active preclinical programme since 2017.All drug development companies actively manage their portfolios to ensure resources are directed as efficiently as possible. Despite a significant clinical research effort in Friedreich’s Ataxia, other research programmes within BioMarin continue to demonstrate a clearer path forward. It is with great regret that we are unable to pursue this programme further.
Henry Fuchs -- Executive Vice President and Chief Medical Officer: After my preclinical research and testing, we have determined this in the best interest of our R&D organization to put our resources toward products that have demonstrated a clear path forward. To take decisions very seriously, we will continue to take a disciplined approach when determining which portfolio assets align with our stage of growth and in the best interest of our shareholders and patients.
Henry Fuchs -- Executive Vice President and Chief Medical Officer: After my preclinical research and testing, we have determined this in the best interest of our R&D organization to put our resources toward products that have demonstrated a clear path forward. To take decisions very seriously, we will continue to take a disciplined approach when determining which portfolio assets align with our stage of growth and in the best interest of our shareholders and patients.
Friday, August 2, 2019
Low frataxin mRNA expression is associated with inflammation and oxidative stress in patients with type 2 diabetes
Etiane Tatsch José A.M. De Carvalho Yãnaí S. Bollick Thiago Duarte Marta M.M.F. Duarte Rodrigo A. Vaucher Melissa O. Premaor Fabio V. Comim Rafael N. Moresco; Diabetes Metab Res Rev. 2019;e3208. doi:10.1002/dmrr.3208.
Type 2 diabetes patients with low frataxin mRNA levels showed a high degree of inflammation and oxidative stress. It is speculated that frataxin deficiency in T2D patients can contribute to the imbalance in mitochondrial iron homeostasis leading to the acceleration of oxidative stress and inflammation.
Type 2 diabetes patients with low frataxin mRNA levels showed a high degree of inflammation and oxidative stress. It is speculated that frataxin deficiency in T2D patients can contribute to the imbalance in mitochondrial iron homeostasis leading to the acceleration of oxidative stress and inflammation.
Thursday, August 1, 2019
REGENXBIO Announces New License Agreement with Pfizer for the Treatment of Friedreich's Ataxia Using NAV® AAV9 Vector
ROCKVILLE, Md., July 31, 2019 /PRNewswire/ -- REGENXBIO Inc. (Nasdaq: RGNX), a leading clinical-stage biotechnology company seeking to improve lives through the curative potential of gene therapy based on its proprietary NAV Technology Platform, today announced it entered into a license agreement with Pfizer Inc.
"This license agreement further validates the strength of our intellectual property portfolio and the potential of NAV AAV9 for the treatment of systemic and CNS manifestations of movement disorders," said Kenneth T. Mills, President and Chief Executive Officer of REGENXBIO. "We are pleased to establish our relationship with Pfizer as they advance this program to develop a potential gene therapy treatment for Friedreich's ataxia."
"This license agreement further validates the strength of our intellectual property portfolio and the potential of NAV AAV9 for the treatment of systemic and CNS manifestations of movement disorders," said Kenneth T. Mills, President and Chief Executive Officer of REGENXBIO. "We are pleased to establish our relationship with Pfizer as they advance this program to develop a potential gene therapy treatment for Friedreich's ataxia."
Nrf2 Induction Re-establishes a Proper Neuronal Differentiation Program in Friedreich’s Ataxia Neural Stem Cells
La Rosa Piergiorgio, Russo Marta, D’Amico Jessica, Petrillo Sara, Aquilano Katia, Lettieri-Barbato Daniele, Turchi Riccardo, Bertini Enrico S., Piemonte Fiorella; Frontiers in Cellular Neuroscience, vol 3, 2019 DOI=10.3389/fncel.2019.00356
Frataxin deficiency is the pathogenic cause of Friedreich’s Ataxia, an autosomal recessive disease characterized by the increase of oxidative stress and production of free radicals in the cell. Although the onset of the pathology occurs in the second decade of life, cognitive differences and defects in brain structure and functional activation are observed in patients, suggesting developmental defects to take place during fetal neurogenesis. Here we describe impairments in proliferation, stemness potential and differentiation in neural stem cells isolated from the embryonic cortex of the Frataxin Knockin/Knockout mouse, a disease animal model whose slow-evolving phenotype makes it suitable to study pre-symptomatic defects that may manifest before the clinical onset. We demonstrate that enhancing the expression and activity of the antioxidant response master regulator Nrf2 ameliorates the phenotypic defects observed in neural stem cells, re-establishing a proper differentiation program.
Frataxin deficiency is the pathogenic cause of Friedreich’s Ataxia, an autosomal recessive disease characterized by the increase of oxidative stress and production of free radicals in the cell. Although the onset of the pathology occurs in the second decade of life, cognitive differences and defects in brain structure and functional activation are observed in patients, suggesting developmental defects to take place during fetal neurogenesis. Here we describe impairments in proliferation, stemness potential and differentiation in neural stem cells isolated from the embryonic cortex of the Frataxin Knockin/Knockout mouse, a disease animal model whose slow-evolving phenotype makes it suitable to study pre-symptomatic defects that may manifest before the clinical onset. We demonstrate that enhancing the expression and activity of the antioxidant response master regulator Nrf2 ameliorates the phenotypic defects observed in neural stem cells, re-establishing a proper differentiation program.
Tuesday, July 30, 2019
The neuroprotective mechanisms and effects of sulforaphane
Klomparens EA, Ding Y.; Brain Circ 2019;5:74-83 DOI: 10.4103/bc.bc_7_19
Sulforaphane (SFN) is a phytochemical found in cruciferous vegetables. It has been shown to have many protective effects against many diseases, including multiple types of cancer. SFN is a potent activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response element (ARE) genetic pathway. Upregulation of Nrf2-ARE increases the availability of multiple antioxidants. A substantial amount of preclinical research regarding the ability of SFN to protect the nervous system from many diseases and toxins has been done, but only a few small human trials have been completed. Preclinical data suggest that SFN protects the nervous system through multiple mechanisms and may help reduce the risk of many diseases and reduce the burden of symptoms in existing conditions. This review focuses on the literature regarding the protective effects of SFN on the nervous system. A discussion of neuroprotective mechanisms is followed by a discussion of the protective effects elicited by SFN administration in a multitude of neurological diseases and toxin exposures. SFN is a promising neuroprotective phytochemical which needs further human trials to evaluate its efficacy in preventing and decreasing the burden of many neurological diseases.
Sulforaphane (SFN) is a phytochemical found in cruciferous vegetables. It has been shown to have many protective effects against many diseases, including multiple types of cancer. SFN is a potent activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response element (ARE) genetic pathway. Upregulation of Nrf2-ARE increases the availability of multiple antioxidants. A substantial amount of preclinical research regarding the ability of SFN to protect the nervous system from many diseases and toxins has been done, but only a few small human trials have been completed. Preclinical data suggest that SFN protects the nervous system through multiple mechanisms and may help reduce the risk of many diseases and reduce the burden of symptoms in existing conditions. This review focuses on the literature regarding the protective effects of SFN on the nervous system. A discussion of neuroprotective mechanisms is followed by a discussion of the protective effects elicited by SFN administration in a multitude of neurological diseases and toxin exposures. SFN is a promising neuroprotective phytochemical which needs further human trials to evaluate its efficacy in preventing and decreasing the burden of many neurological diseases.
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