New treatments for cystic fibrosis: Where do we are?
|
|
- Barnaby Gavin Carter
- 6 years ago
- Views:
Transcription
1 New treatments for cystic fibrosis: Where do we are? Aleksander Edelman INSEM U845 Hôpital Necker (Broussais) Paris Académie de Pharmacie 2013
2 Thanks to: Laboratoire U845 équipe Edelman: S. Bitam I. Pranke N. Servel M. Faria da Cunha A. Hatton J. Simonin C. Moquereau D. Tondelier I.Sermet-Gaudelus J. Fritsch Mc Gill University, Quebec: G Lukacs Institut Pasteur, Paris: G Faure, H Xu Université de Poitiers: F. Becq C. Norez IBB, PAS, Warsaw, Poland: N. Odolczyk G. Wieczorek P. Zielenkiewicz German cancer research centre H Herrmann
3 Cystic Fibrosis Genetic disease associated with mutations in CFT (F508del in70% of patients) Mutations cause : Abnormal fluid transport in epithelia Chronic infection & inflammation Pulmonary disease Hepatobiliary disease Pancreatic insufficiency Meconial ileus Male infertility Sweat test
4 folding energy CFT protein Band C (170kD) Band B (150kD) iordan Lukacs Thomas Skach Cyr CO-TANSLATIONAL NBD1 folding M1 M1 M2 M1 M2 POST-TANSLATIONAL 170kDa NBD1-MSD2 interface native CFT apical membrane of epithelial cells camp-dependent Cl - M1 M2 channel N1 N1 N2 N1 N2 N1
5 CFT-related abnormalities Abnormal mucus Abnormal antimicrobial defense Abnormal ASL CFT Abnormal glycosylation Abnormal cystoskeleton Mitochondrial abnormalities Protein traffic Oxidative stress Noyau Chronic inflammation NF-kB TNF-a, IL-1b, oxydants, proteases
6 > 1900 mutations Class of mutations
7 Biosynthetic pathway for CFT Cl - Cl - Wt-CFT : 20% of protein arrives to the plasma membrane Lysosomal degradation vesicles F508-CFT : Trans Golgi isoform C 1% of protein arrives to the plasma membrane Proteasomal degradation Cis Golgi isoform B (99%) ibosome E Form A
8 Biosynthetic pathway for CFT Cl - Potentiator: suitable for class 3 and 4 e.g. G551D Lysosomal degradation vesicles Trans Golgi isoform C Proteasomal degradation isoform B (99%) ibosome Cis Golgi E Correctors: suitable for class 2 Form A
9 Strategies to find correcting compounds High-throuput screening Cell based assays function HeLa cells, FT primary cells in culture Modelling Vertex: VX-809, C4..
10 Experimental approaches Functional assays Biochemical assays Fluorescent assay Short circuit current Immunoblot of Amiloride IBMX/Fsk inh 172
11 folding energy CFT vs. F508CFT WT CFT CO-TANSLATIONAL POST-TANSLATIONAL native CFT M1 M1 M2 M1 M2 M1 M2 N1 N1 N2 N1 N2 N1 CO-TANSLATIONAL POST-TANSLATIONAL ΔF508 CFT M1 impaired NBD1 folding M1 M2 impaired NBD1-MSD2 interface M1 M2 non-native CFT M1 M2 Δ Δ Δ N2 Δ N2 maneuver primary target rescue effect Courtesy Gergely Lukacs, McGill University; abeh et al Cell 2012
12 Corrector combination targeting distinct structural defects synergistically rescue ΔF508 CFT expression defect in BHK cells CO-TANSLATIONAL POST-TANSLATIONAL M1 Δ M1 Δ M2 M1 Δ M2 N2 M1 Δ M2 N2 ΔF508-CFT CCs (glycerol, etc) Class-I: VX809, C18, C3 Class II (C4, C13, corr-ii) Courtesy Gergely Lukacs, McGill University
13 Corrector combinations robustly rescue ΔF508 CFT expression defect in intestinal organoids from homozygous CF patients 0 min 60 min Normalized area (%) calcein green Change in volume= index of CFT function DMSO 150 VX809 Myo (chemical chapron) myo +VX809 +C4 myo+vx809+c4 +Inh myo+vx809 VX809 myo DMSO myo+vx809+c4+inh Time (min) in the presence of camp Okiyoneda et al Nat Chem Biol 2013
14 Conclusions (1) Correctors decrease the energy of CFT folding Correction of 10-15% is currently achieved by individual compounds Combinations of correctors will be necessary to treat CF patients with F508 mutation
15 < 1900 mutations Classes of mutations
16 VX-770 (ivacaftor) VX-770 acted as a potentiator of G551D- and F508del CFT in recombinant cells. Van Goor F et al. PNAS 2009;106: by National Academy of Sciences
17 espiratory function: FEV1 Clinical assay: phase 3 for G551D or G551D- F508 patients Close to 300 patients I. Sermet-Gaudelus Eur esp ev 2013 : 22( 127) p. 66 I. Sermet-Gaudelus Eur esp ev 2013 : 22( 127) p. 66
18 Sweat test concentration I. Sermet-Gaudelus Eur esp ev 2013 : 22( 127) p. 66
19 Conclusions (2) Ivacaftor is suitable for treatment of CF patients with G551D mutation (3000 patients worldwide) Potentiator + Correctors will be probably necessary for F508 treatments
20 Strategies to find correcting compounds High-throuput screening Hypothesis-driven screening Cell based assays function HeLa cells, FT primary cells in culture Modelling in silico screening Modelling Cell based assays function HeLa cells, FT primary cells in culture Vertex: VX-809, C4.. Odolczyk et al EMBO Mol Med 2013
21 folding energy Hypothesis-driven research Unwanted interaction between houskeeping proteins and DF508NBD1 prevents the delivery of DF508CFT to the plasma membrane WT CFT native CFT M1 M1 M2 M1 M2 M1 M2 N1 N1 N2 N1 N2 N1 impaired NBD1 folding impaired NBD1-MSD2 interface non-native CFT ΔF508 M1 Δ M1 p Δ M2 M1 Δ M2 N2 M1 Δ M2 N2 p: keratin 8, cytoskeletal protein Odolczyk et al EMBO Mol Med 2013
22 Keratin 8, a candidate for unwanted interaction with F508CFT Expression and/or network of keratin 8 is altered in CF cells (Colas et al Hum&Mol Gen 2012) HeLa cells K8 CFT Merge WT F508del Davezac et al Proteomics 2004
23 Keratin 8, a candidate for unwanted interaction with F508CFT Keratin 8 form a complex with F508-CFT (Colas et al Hum&Mol Gen 2012) Keratin 8, modifier gene in CF (Stanke et al BMC Med Genet. 2011) Changing keratin 18 network corrects the functional defect of mutated CFT (Davezc et al Proteomics 2004, Lipecka et al JPET 2006, Hamdaoui et al BJP 2011)
24 K8 interacts with F508CFT in primary culture of human bronchial cells K8- F508-CFT proximity healthy F508del patient apical side apical side Z y Z y Z Z y DNA proximity ligation assay Colas et al Hum Mol Gen 2012
25 Strategy to find the targets for correction: in silico approach WT-NBD1 DF508-NBD1 TY577 TP496 POCKET 1 TY577 TP496 POCKET 2 PHE494 PHE494 Wieczorek G., Wieczorek&Zielenkiewicz Odolczyk N., P. Zielenkiewicz, J Cyst IBB, Fibrosis Warsaw 2011
26 Hydrophobic surface of NBD1 ΔF508 CFT Dock-in: from to 4 compounds POCKET 1 TY577 TP496 POCKET 2 PHE494 Odolczyk et al EMBO Mol Med 2013; Wieczorek&Zielenkiewicz J Cyst Fibrosis 2011
27 Cl - secretion after treatment of CF cells with compound (Isc) Amiloride IBMX/Fsk inh 172 Amiloride IBMX/Fsk inh µa/cm 2 2 µa/cm 2 10 minutes 10 minutes untreated (1mM/24h) Treatement with restores CFT function in CF cells Odolczyk et al EMBO Mol Med 2013
28 Changes in the stability of F508NBD1 by (by hydrogen-deuterium exchange MS) F508NBD1 F508 HDex rate increased 12% HDex rate decreased ( -1%) HDex NS changed ΔF508-NBD Odolczyk et al EMBO Mol Med 2013
29 Targeting protein protein interactions to rescue ΔF508 CFT EMBO Molecular Medicine Volume 5; , 2013
30 Summary and conclusion (3) K8 interacts with DF508CFT Preventing interaction K8- DF508CFT delivers DF508CFT to the plasma membrane New correctors do not stablize F508NBD1 Keratin 8-DF508CFT interaction constitutes a target for pharmacotherapy of CF patients bearing DF508 mutation
31 Conclusions Combinations of correctors and potentiators will be necessary for treatments New correctors need to diminish energy of folding necessary for biosynthesis of CFT interrupt unwanted Thank you for your attention.
32 Functional studies : Nasal Potential Difference (1) Experimental protocol 10µM NPD 0 Day 0 F508del Day 7 and 8 Hour 0 and 24 NPD day 9 Day 9 Hour 48
33 Functional studies : Nasal Potential Difference (2) amiloride low Cl - inh-172 DIDS amiloride low Cl - inh-172 DIDS Time (min.) Time (min.) Day 0 Day 9
34 Corrector combination targeting distinct structural defects synergistically rescue ΔF508 CFT expression defect in BHK cells CO-TANSLATIONAL POST-TANSLATIONAL M1 Δ M1 Δ M2 M1 Δ M2 N2 M1 Δ M2 N2 ΔF508 CFT CCs (glycerol, etc) Class-I: VX809, C18, C3 Class II (C4, C13, corr-ii) DF508 WT Gly: C4: VX809: aha C B aatpase Courtesy Gergely Lukacs
CF: Understanding the Biology Curing the Disease
CF: Understanding the Biology Curing the Disease Scott H. Donaldson, MD Associate Professor of Medicine Director, Adult CF Care Center University of North Carolina at Chapel Hill Defining the path Drilling
More informationTransformational Treatments. PRESTON W. CAMPBELL, III, M.D. Executive Vice President for Medical Affairs
Transformational Treatments PRESTON W. CAMPBELL, III, M.D. Executive Vice President for Medical Affairs Symptom-based CF Therapies 45 Median Predicted Survival Age of US Patients with Cystic Fibrosis 41
More informationEFFECT OF FOUR SETS OF DISTINCT MODULATORS ON NON-F508DEL MUTATIONS THAT CAUSE CYSTIC FIBROSIS
EFFECT OF FOUR SETS OF DISTINCT MODULATORS ON NON-F508DEL MUTATIONS THAT CAUSE CYSTIC FIBROSIS BHATT, PRIYANKA; BAILEY, VIOLAINE; DASGUPTA, AFIA; CHIN, JUSTIN; AN, WEILING; BRESILLA, CASTERA; KWOK, IRIS;
More informationCystic Fibrosis the future
Cystic Fibrosis the future Pathophysiologic cascade Abnormal Gene Abnormal CFTR Therapy Gene replacement Protein replacement Gene read through therapy Abnormal sodium chloride & water movement through
More informationA Genetic Approach to the Treatment of Cystic Fibrosis
A Genetic Approach to the Treatment of Cystic Fibrosis Peter Mueller, PhD Chief Scientific Officer and Executive Vice President Global Research and Development Vertex Pharmaceuticals, Incorporated March
More informationRespiratory Pharmacology: Treatment of Cystic Fibrosis
Respiratory Pharmacology: Treatment of Cystic Fibrosis Dr. Tillie-Louise Hackett Department of Anesthesiology, Pharmacology and Therapeutics University of British Columbia Associate Head, Centre of Heart
More informationNACFC investor meeting. Dr Katja Conrath, Therapeutic Head CF Dr Piet Wigerinck, CSO NACFC November 2017 Copyright 2017 Galapagos NV
NACFC investor meeting Dr Katja Conrath, Therapeutic Head CF Dr Piet Wigerinck, CSO NACFC 2017 2 November 2017 Copyright 2017 Galapagos NV Disclaimer This presentation contains forward-looking statements,
More informationEnabling CF Therapeutic Development
Enabling CF Therapeutic Development PRESTON W. CAMPBELL, III, M.D. Executive Vice President for Medical Affairs No Disclosures Cystic Fibrosis In 1955 In 1955 most children with CF did not live long enough
More information"Management and Treatment of Patients with Cystic fibrosis (CF)
"Management and Treatment of Patients with Cystic fibrosis (CF) Dr. Malena Cohen-Cymberknoh Pediatric Pulmonology and CF Center Hadassah Hebrew-University Medical Center Jerusalem, Israel Afula, March
More informationMolecular Basis of Personalized Therapies for CF: Can We Treat All Patients?
CF Europe Meeting Molecular Basis of Personalized Therapies for CF: Can We Treat All Patients? Margarida D Amaral Brussels, 13 June 2015 The CF Pathogenesis Cascade 2 Defective CF Genes Deficient CFTR
More informationVX-809 and Related Corrector Compounds Exhibit Secondary Activity Stabilizing Active F508del-CFTR after Its Partial Rescue to the Cell Surface
Article VX-809 and Related Corrector Compounds Exhibit Secondary Activity Stabilizing Active F508del-CFTR after Its Partial Rescue to the Cell Surface Paul D.W. Eckford, 1,5 Mohabir Ramjeesingh, 1,5 Steven
More informationThe Future of CF Therapy
The Future of CF Therapy Peter J. Mogayzel, Jr., M.D., Ph.D. Eudowood Division of Pediatric Respiratory Sciences The Johns Hopkins School of Medicine Overview The Future of CF Therapy Personalized therapy
More informationWe strive to develop innovative solutions that improve and extend the lives of people with cystic fibrosis
Nivalis Therapeutics, Inc., October 2015 Analyst Breakfast at NACFC We strive to develop innovative solutions that improve and extend the lives of people with cystic fibrosis Disclaimer Regarding Forward
More informationCystic fibrosis (CF) is the most frequent. Ivacaftor treatment in patients with cystic REVIEW. Isabelle Sermet-Gaudelus
Eur Respir Rev 2013; 22: 127, 66 71 DOI: 10.1183/09059180.00008512 CopyrightßERS 2013 REVIEW Ivacaftor treatment in patients with cystic fibrosis and the G551D-CFTR mutation Isabelle Sermet-Gaudelus ABSTRACT:
More informationCystic Fibrosis Foundation Patient Registry 2013
5/9/2015 Targeting CFTR to Treat Cystic Fibrosis: Small Molecule Therapy Mary Ellen Kleinhenz, MD Director, UCSF Adult Cystic Fibrosis Program Professor of Medicine UCSF Division of Pulmonary, Critical
More informationTHE ROLE OF CFTR MUTATIONS IN CAUSING CYSTIC FIBROSIS (CF)
THE ROLE OF CFTR MUTATIONS IN CAUSING CYSTIC FIBROSIS (CF) Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210. Vertex and the Vertex triangle logo are registered trademarks for Vertex
More informationCystic Fibrosis: Progress in Treatment Management. Patrick A. Flume, M.D. Medical University of South Carolina
Cystic Fibrosis: Progress in Treatment Management Patrick A. Flume, M.D. Medical University of South Carolina Disclosures Grant support Mpex Pharmaceuticals, Inc Gilead Sciences, Inc Bayer Healthcare AG
More informationPediatrics Grand Rounds 18 Sept University of Texas Health Science Center. + Disclosure. + Learning Objectives.
Disclosure Dr Donna Willey Courand receives research support from Cystic Fibrosis Therapeutics The Cystic Fibrosis Foundation Children with Special Health Care Needs Cystic Fibrosis 05: Improving Survival
More informationPULMONARY SURFACTANT, ALPHA 1 ANTITRYPSIN INHIBITOR DEFICIENCY, AND CYSTIC FIBROSIS DR. NABIL BASHIR BIOCHEMISTRY/RESPIRATORY SYSTEM
PULMONARY SURFACTANT, ALPHA 1 ANTITRYPSIN INHIBITOR DEFICIENCY, AND CYSTIC FIBROSIS DR. NABIL BASHIR BIOCHEMISTRY/RESPIRATORY SYSTEM Pulmonary surfactant Pulmonary surfactant is (phospholipoprotein) complex
More informationDisclosures. Advances in the Management of Cystic Fibrosis: A Closer Look at the Roles of CFTR Modulation Therapy 10/28/2016
Advances in the Management of Cystic Fibrosis: A Closer Look at the Roles of CFTR Modulation Therapy Susanna A McColley, MD Associate Chief Research Officer Stanley Manne Children s Research Institute
More informationTargeted therapies to improve CFTR function in cystic fibrosis
Brodlie et al. Genome Medicine (2015) 7:101 DOI 10.1186/s13073-015-0223-6 REVIEW Targeted therapies to improve CFTR function in cystic fibrosis Malcolm Brodlie 1*, Iram J. Haq 2, Katie Roberts 2 and J.
More informationCystic fibrosis: hitting the target
Cystic fibrosis: hitting the target Heartland Collaborative Annual Meeting Friday, October 5, 2012 Thomas Ferkol MD 1938 1953 Cystic fibrosis: a historical timeline Cystic fibrosis (CF) of the pancreas
More informationMedical Policy An independent licensee of the Blue Cross Blue Shield Association
Cystic Fibrosis Transmembrane Page 1 of 11 Medical Policy An independent licensee of the Blue Cross Blue Shield Association Title: Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Prime Therapeutics
More informationCase Study What is the Relationship Between the Cell Membrane and Cystic Fibrosis?
Names: Date: Case Study What is the Relationship Between the Cell Membrane and Cystic Fibrosis? Dr. Weyland examined a six month old infant that had been admitted to University Hospital earlier in the
More informationNorth American Cystic Fibrosis Conference 27 October Noreen R Henig, MD Chief Development Officer ProQR Therapeutics
Proof of Concept Study to Demonstrate the Effects of QR-010 on Nasal Potential Difference in Subjects With Cystic Fibrosis with the F508del CFTR Mutation Noreen R Henig, MD Chief Development Officer ProQR
More informationHOW DISEASE ALTERING THERAPY IS CHANGING THE GOALS OF TREATMENT IN CF
HOW DISEASE ALTERING THERAPY IS CHANGING THE GOALS OF TREATMENT IN CF Peter D. Sly MBBS, MD, FRACP, DSc OUTLINE Goals of CF treatment Drivers of early disease neutrophilic inflammation oxidative stress
More informationNorth American Cystic Fibrosis Conference 27 October Noreen R Henig, MD Chief Development Officer ProQR Therapeutics
Proof of Concept Study to Demonstrate the Effects of QR-010 on Nasal Potential Difference in Subjects With Cystic Fibrosis with the F508del CFTR Mutation Noreen R Henig, MD Chief Development Officer ProQR
More informationA Case of Cystic Fibrosis
Name(s) Date A Case of Cystic Fibrosis Dr. Weyland examined a six month old infant that had been admitted to University Hospital earlier in the day. The baby's parents had brought young Zoey to the emergency
More informationPreclinical in vitro Evaluation: Combination FDL169/FDL176 is Superior to Tezacaftor/Ivacaftor
Mike Zawistoski @ MZ Sports Shots Preclinical in vitro Evaluation: Combination /FDL176 is Superior to Tezacaftor/Ivacaftor Flatley Discovery Lab Preclinical in vitro Evaluation of CFTR Modulator Combinations
More informationPharmacogenomics in Rare Diseases: Development Strategy for Ivacaftor as a Therapy for Cystic Fibrosis
Pharmacogenomics in Rare Diseases: Development Strategy for Ivacaftor as a Therapy for Cystic Fibrosis Federico Goodsaid Vice President Strategic Regulatory Intelligence Vertex Pharmaceuticals Is there
More informationA Quick Guide to the. I507del. Mutation CFTR SCIENCE
A Quick Guide to the I507del Mutation CFTR SCIENCE 2016 Vertex Pharmaceuticals Incorporated VXR-HQ-02-00045a(1) 03/2016 Loss of CFTR activity is the underlying cause of cystic fibrosis (CF) 1 Spectrum
More informationSupplementary appendix
Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Moss RB, Flume PA, Elborn JS, et al, on behalf
More informationCost-effectiveness of Ivacaftor (Kalydeco ) for the treatment of cystic fibrosis in patients age 6 years and older who have the G551D mutation
Cost-effectiveness of Ivacaftor (Kalydeco ) for the treatment of cystic fibrosis in patients age 6 years and older who have the G551D mutation January 2013 1. A rapid review submission on the drug ivacaftor
More informationONLINE SUPPLEMENT Title: CFTR dysfunction induces vascular endothelial growth factor synthesis in airway epithelium
ONLINE SUPPLEMENT Title: CFTR dysfunction induces vascular endothelial growth factor synthesis in airway epithelium Martin C, Coolen N, Wu YZ, Thévenot G, Touqui L, PrulièreEscabasse V, Papon JF, Coste
More informationCystic Fibrosis Update
Cystic Fibrosis Update More than Decades of Discovery Dr. Raj Padman Professor of Pediatric TJU Board certified in Pediatrics, Pulmonology, and Sleep Medicine Dupont, Kosciusko Community, Lutheran, Rehabilitation,
More informationNIH Public Access Author Manuscript Curr Mol Med. Author manuscript; available in PMC 2011 June 14.
NIH Public Access Author Manuscript Published in final edited form as: Curr Mol Med. 2010 February ; 10(1): 82 94. Protein Processing and Inflammatory Signaling in Cystic Fibrosis: Challenges and Therapeutic
More informationTHE ROLE OF CFTR MUTATIONS IN CAUSING CYSTIC FIBROSIS (CF)
THE ROLE OF CFTR MUTATIONS IN CAUSING CYSTIC FIBROSIS (CF) Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210. Vertex and the Vertex triangle logo are registered trademarks of Vertex
More informationEvaluation of Patients with Diffuse Bronchiectasis
Evaluation of Patients with Diffuse Bronchiectasis Dr. Patricia Eshaghian, MD Assistant Clinical Professor of Medicine Director, UCLA Adult Cystic Fibrosis Affiliate Program UCLA Division of Pulmonary
More informationRepairing the basic defect in cystic fibrosis one approach is not enough
REVIEW ARTICLE Repairing the basic defect in cystic fibrosis one approach is not enough Carlos M. Farinha 1 and Paulo Matos 1,2 1 BioISI Biosystems & Integrative Sciences Institute, Faculty of Sciences,
More informationA Quick Guide to the G A. Mutation CFTR SCIENCE
A Quick Guide to the 1717-1G A Mutation FR SIENE 2016 Vertex Pharmaceuticals Incorporated VXR-HQ-02-00045a(1) 03/2016 Loss of FR activity is the underlying cause of cystic fibrosis (F) 1 Spectrum of Phenotypes
More informationThe role of Lipoxin A4 in Cystic Fibrosis Lung Disease
Volume No: 6, Issue: 7, March 2013, e201303018, http://dx.doi.org/10.5936/csbj.201303018 CSBJ The role of Lipoxin A4 in Cystic Fibrosis Lung Disease Valérie Urbach a,b,*, Gerard Higgins a, Paul Buchanan
More informationMedical Policy An independent licensee of the Blue Cross Blue Shield Association
Cystic Fibrosis Transmembrane Page 1 of 13 Medical Policy An independent licensee of the Blue Cross Blue Shield Association Title: Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Prime Therapeutics
More informationSupplementary Appendix
Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Donaldson SH, Bennett WD, Zeman KL, et al. Mucus clearance
More informationSymdeko. Symdeko (tezacaftor and ivacaftor) Description
Federal Employee Program 1310 G Street, N.W. Washington, D.C. 20005 202.942.1000 Fax 202.942.1125 5.45.10 Subject: Symdeko Page: 1 of 5 Last Review Date: June 22, 2018 Symdeko Description Symdeko (tezacaftor
More informationCystic Fibrosis Diagnosis and Treatment
Cystic Fibrosis Diagnosis and Treatment Financial Disclosures Personal financial relationships with commercial interests relevant to medicine, within the past 3 years: NJH site PI for AstraZeneca. As faculty
More informationBriefing Document. FDA Pulmonary - Allergy Drugs Advisory Committee
FDA Advisory Committee Briefing Materials Page 1 of 157 Briefing Document FDA Pulmonary - Allergy Drugs Advisory Committee Ivacaftor for the Treatment of Cystic Fibrosis in Patients Age 6 Years and Older
More informationKalydeco. Kalydeco (ivacaftor) Description
Federal Employee Program 1310 G Street, N.W. Washington, D.C. 20005 202.942.1000 Fax 202.942.1125 5.45.03 Subject: Kalydeco Page: 1 of 6 Last Review Date: November 30, 2018 Kalydeco Description Kalydeco
More informationPhase 1 and 2 Data for Triple Combination Regimens Demonstrate Improvements in Lung Function and Other Measures in CF Patients
Phase 1 and 2 Data for Triple Combination Regimens Demonstrate Improvements in Lung Function and Other Measures in CF Patients July 18, 2017 Agenda Introduction Michael Partridge, VP Investor Relations
More informationLiver Disease in Cystic Fibrosis
Liver Disease in Cystic Fibrosis Basic Overview Clinical Aspects Management What Is Cystic Fibrosis? Autosomal recessive disease W-1:3000, H-1:10,000, AA-1:15,000 Mutations of CFTR defective Cl - transport
More informationIVACAFTOR THE ISRAELI EXPERIENCE ADI DAGAN MD THE ISRAELI CF CENTER SHEBA MEDICAL CENTER, TEL-HASHOMER
IVACAFTOR THE ISRAELI EXPERIENCE ADI DAGAN MD THE ISRAELI CF CENTER SHEBA MEDICAL CENTER, TEL-HASHOMER February 21, 2014 U.S. Food and Drug Administration Approves KALYDECO (ivacaftor) for Use in Eight
More informationDeleterious impact of Pseudomonas aeruginosa on cystic fibrosis transmembrane conductance regulator function and rescue in airway epithelial cells
ORIGINAL ARTICLE CYSTIC FIBROSIS Deleterious impact of Pseudomonas aeruginosa on cystic fibrosis transmembrane conductance regulator function and rescue in airway epithelial cells Nguyen Thu Ngan Trinh,,5,
More informationWhat is Cystic Fibrosis? CYSTIC FIBROSIS. Genetics of CF
What is Cystic Fibrosis? CYSTIC FIBROSIS Lynne M. Quittell, M.D. Director, CF Center Columbia University Chronic, progressive and life limiting autosomal recessive genetic disease characterized by chronic
More informationANALYST & INVESTOR EVENT NACFC 2016, Orlando, Florida
ANALYST & INVESTOR EVENT NACFC 216, Orlando, Florida Date: October 27th, 216 Presenters: Daniel de Boer, Noreen Henig and JP Clancy Agenda Overview and introduction by Daniel de Boer The relevance of the
More informationCHEST Recent Advances in Chest Medicine
CHEST Recent Advances in Chest Medicine Cystic Fibrosis Transmembrane Conductance Regulator Intracellular Processing, Trafficking, and Opportunities for Mutation-Specific Treatment Mark P. Rogan, MD ;
More informationA review of Cystic Fibrosis
A review of Cystic Fibrosis Jennifer Landry md F.R.C.P.(C) Pulmonary & Critical Care Medicine McGill University Health Center Cystic Fibrosis One of the most common lethal inherited AR disorders in the
More informationStudy of different types of ubiquitination
Study of different types of ubiquitination Rudi Beyaert (rudi.beyaert@irc.vib-ugent.be) VIB UGent Center for Inflammation Research Ghent, Belgium VIB Training Novel Proteomics Tools: Identifying PTMs October
More informationPediatrics Grand Rounds 13 November University of Texas Health Science Center at San Antonio. Learning Objectives
Nationwide Newborn Screening for Cystic Fibrosis: Finally Creating an Opportunity for All Patients to Have Better Outcomes Philip M Farrell, MD, PhD* University of Wisconsin-Madison *No disclosures other
More informationOral Cystic Fibrosis Modulators
Oral Cystic Fibrosis Modulators Goals: To ensure appropriate drug use and limit to patient populations in which they have demonstrated to be effective and safe. To monitor for clinical response for appropriate
More informationT he cystic fibrosis transmembrane conductance regulator
971 RESPIRATORY PHYSIOLOGY Nasal airway ion transport is linked to the cystic fibrosis phenotype in adult patients I Fajac, D Hubert, D Guillemot, I Honoré, T Bienvenu, F Volter, J Dall Ava-Santucci, D
More informationCYSTIC FIBROSIS OBJECTIVES NO CONFLICT OF INTEREST TO DISCLOSE
CYSTIC FIBROSIS Madhu Pendurthi MD MPH Staff Physician, Mercy Hospital Springfield, MO NO CONFLICT OF INTEREST TO DISCLOSE OBJECTIVES Epidemiology of Cystic Fibrosis (CF) Genetic basis and pathophysiology
More informationPharmacy Policy Bulletin
Pharmacy Policy Bulletin Title: Policy #: Cystic Fibrosis Agents (Kalydeco, Orkambi ) Rx.01.117 Application of pharmacy policy is determined by benefits and contracts. Benefits may vary based on product
More informationChapt. 10 Cell Biology and Biochemistry. The cell: Student Learning Outcomes: Describe basic features of typical human cell
Chapt. 10 Cell Biology and Biochemistry Cell Chapt. 10 Cell Biology and Biochemistry The cell: Lipid bilayer membrane Student Learning Outcomes: Describe basic features of typical human cell Integral transport
More informationGoals Basic defect Pathophysiology Clinical i l signs and symptoms Therapy
CYSTIC FIBROSIS Lynne M. Quittell, M.D. Director, CF Center Columbia University Goals Basic defect Pathophysiology Clinical i l signs and symptoms Therapy What is Cystic Fibrosis? Chronic, progressive
More informationThe ecology of disease interactions in CF
1/44 The ecology of disease in CF University of Utah Department of Mathematics and Department of Biology September 4, 2014 2/44 The big questions in ecology Why are there so many species? Charley Harper
More informationGLPG1837 in Subjects with Cystic Fibrosis (CF) and the G551D Mutation: results from a Phase II study (SAPHIRA1)
GLPG1837 in Subjects with Cystic Fibrosis (CF) and the G551D Mutation: results from a Phase II study (SAPHIRA1) ECFS, Sevilla, Spain 9 June 2017 Jane Davies on behalf of the SAPHIRA1 Study Team Copyright
More informationBIOL 4374/BCHS 4313 Cell Biology Exam #1 February 13, 2001
BIOL 4374/BCHS 4313 Cell Biology Exam #1 February 13, 2001 SS# Name This exam is worth a total of 100 points. The number of points each question is worth is shown in parentheses. Good luck! 1. (2) The
More informationPA Update: Oral Cystic Fibrosis Modulators
Copyright 2012 Oregon State University. All Rights Reserved Drug Use Research & Management Program Oregon State University, 500 Summer Street NE, E35 Salem, Oregon 97301-1079 Phone 503-947-5220 Fax 503-947-1119
More informationHow does cellular volume regulation works: Contribution of anoctamins, LRRC8A and CFTR
S Februar 2017 Current projects How does cellular volume regulation works: Contribution of anoctamins, LRRC8A and CFTR Recent results from our lab indicate a central role of anoctamins such as ANO1, ANO6
More informationCystic Fibrosis. Na+ 2Cl - K+ Na+ Na+
1 Cystic Fibrosis I. Overview of cystic fibrosis Among Caucasians, about one out of twenty people carry the gene for cystic fibrosis (CF), and one of 2,000 to 4,000 people is afflicted with the recessive
More informationAdvances in CF therapies and their effect on GI manifestations. Presenter Disclosure Daniel Gelfond, MD Relationship related to this presentation
Advances in CF therapies and their effect on GI manifestations Daniel Gelfond, MD University of Rochester WNY Pediatric Gastroenterology Presenter Disclosure Daniel Gelfond, MD Relationship related to
More informationCystic Fibrosis. Jennifer McDaniel, BS, RRT-NPS
Cystic Fibrosis Jennifer McDaniel, BS, RRT-NPS Overview Cystic fibrosis is the most common fatal, inherited disease in the U. S. CF results from a defective autosomal recessive gene One copy of gene =
More informationSelective Activation of Cystic Fibrosis Transmembrane Conductance Regulator Cl - and HCO 3 - Conductances
JOP. J. Pancreas (Online) 2001; 2(4 Suppl):212218. Selective Activation of Cystic Fibrosis Transmembrane Conductance Regulator Cl and HCO 3 Conductances MallaReddy M Reddy 1, Paul M Quinton 1,2 1 Department
More informationOrkambi. Orkambi (lumacaftor/ivacaftor) Description
Federal Employee Program 1310 G Street, N.W. Washington, D.C. 20005 202.942.1000 Fax 202.942.1125 5.45.06 Subject: Orkambi Page: 1 of 6 Last Review Date: November 30, 2018 Orkambi Description Orkambi (lumacaftor/ivacaftor)
More information1. to understand how proteins find their destination in prokaryotic and eukaryotic cells 2. to know how proteins are bio-recycled
Protein Targeting Objectives 1. to understand how proteins find their destination in prokaryotic and eukaryotic cells 2. to know how proteins are bio-recycled As a protein is being synthesized, decisions
More informationYou Can Observe a Lot By Just Watching. Wayne J. Morgan, MD, CM
You Can Observe a Lot By Just Watching Wayne J. Morgan, MD, CM Disclosures Genentech Epidemiological Study of Cystic Fibrosis, Scientific Advisory Group CF Foundation Data Safety Monitoring Board Registry/Comparative
More informationSupplemental Figure 1. Western blot analysis indicated that MIF was detected in the fractions of
Supplemental Figure Legends Supplemental Figure 1. Western blot analysis indicated that was detected in the fractions of plasma membrane and cytosol but not in nuclear fraction isolated from Pkd1 null
More informationMargarida D Amaral Llsboa, 26 Novembro 2016
Semana Europeia da Fibrose Quística Jornada de Divulgação em Fibrose Quística Novos Fármacos Moduladores da Proteína CFTR Margarida D Amaral Llsboa, 26 Novembro 2016 The CF Pathogenesis Cascade 2 Defective
More informationCystic Fibrosis. Presented by: Chris Belanger & Dylan Medd
Cystic Fibrosis Presented by: Chris Belanger & Dylan Medd Outline What is Cystic Fibrosis? Signs, Symptoms & Diagnosis Who does it effect? General effects on daily life Managing Cystic Fibrosis Exercise
More informationProblem Set #5 4/3/ Spring 02
Question 1 Chloroplasts contain six compartments outer membrane, intermembrane space, inner membrane, stroma, thylakoid membrane, and thylakoid lumen each of which is populated by specific sets of proteins.
More informationLumacaftor and ivacaftor in the management of patients with cystic fibrosis: current evidence and future prospects
601934TAR0010.1177/1753465815601934Therapeutic Advances in Respiratory DiseaseKuk and Taylor-Cousar research-article2015 Therapeutic Advances in Respiratory Disease Review Lumacaftor and ivacaftor in the
More informationEfficacy of NaCl nebulized hypertonic solutions in cystic fibrosis
Acta Biomed 2014; Vol. 85, Supplement 4: 10-18 Mattioli 1885 Original article Efficacy of NaCl nebulized hypertonic solutions in cystic fibrosis Azienda Ospedaliero Universitaria Policlinico, DAI Scienze
More informationCellular mechanisms for electrolyte and water homeostasis
Cellular mechanisms for electrolyte and water homeostasis Objectives: Principle of Na + and water transport Amiloride sensitive Na + Channels CFTR and transepithelial Cl transport Aquaporins in water homeostasis
More informationGlycoprotein Maturation and Quality Control in the Endoplasmic Reticulum Dr. Daniel Hebert
Glycoprotein Maturation and Quality Control in the Endoplasmic Reticulum Department of Biochemistry and Molecular Biology University of Massachusetts, USA 1 Intracellular protein trafficking Plasma membrane
More informationA Quick Guide to the. CFTRdele2,3. Mutation CFTR SCIENCE
Quick uide to the FRdele2,3 Mutation FR SIENE 2016 Vertex Pharmaceuticals Incorporated VXR-HQ-02-00045a(1) 03/2016 Loss of FR activity is the underlying cause of cystic fibrosis (F) 1 Spectrum of Phenotypes
More informationA randomized placebo-controlled trial of miglustat in cystic fibrosis based on nasal potential difference
Journal of Cystic Fibrosis 11 (2012) 231 236 www.elsevier.com/locate/jcf Original Article A randomized placebo-controlled trial of miglustat in cystic fibrosis based on nasal potential difference Anissa
More informationA Quick Guide to the 621+1G T. Mutation CFTR SCIENCE
Quick uide to the 621+1 Mutation FR SIENE 2016 Vertex Pharmaceuticals Incorporated VXR-HQ-02-00045a(1) 03/2016 Loss of FR activity is the underlying cause of cystic fibrosis (F) 1 Spectrum of Phenotypes
More informationChapter 13: Vesicular Traffic
Chapter 13: Vesicular Traffic Know the terminology: ER, Golgi, vesicle, clathrin, COP-I, COP-II, BiP, glycosylation, KDEL, microtubule, SNAREs, dynamin, mannose-6-phosphate, M6P receptor, endocytosis,
More informationThe Cystic Fibrosis Gene. about. CF is one of the most common genetic diseases that cause death in both children and
Gill1 Peter Gill Malory Klocke Research Paper 02 August, 2011 The Cystic Fibrosis Gene Cystic fibrosis, better known as CF, is a genetic disease most people know very little about. CF is one of the most
More informationCYSTIC FIBROSIS (CF) COMPLICATIONS BEYOND THE LUNGS. A Resource for the CF Center Care Team
CYSTIC FIBROSIS (CF) COMPLICATIONS BEYOND THE LUNGS A Resource for the CF Center Care Team Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210. Vertex and the Vertex triangle logo
More informationReview. Ion channel regulators for the treatment of. Christiane De Boeck 1 & Harry Cuppens 2
Review Ion channel regulators for the treatment of cystic fibrosis Cystic fibrosis is a life-shortening hereditary disease caused by mutations in the cystic fibrosis transmembrane conductance regulator
More informationIntracellular Compartments and Protein Sorting
Intracellular Compartments and Protein Sorting Intracellular Compartments A eukaryotic cell is elaborately subdivided into functionally distinct, membrane-enclosed compartments. Each compartment, or organelle,
More informationCystic Fibrosis Impact on Cellular Function
John Carroll University Carroll Collected Senior Honors Projects Theses, Essays, and Senior Honors Projects Spring 2014 Cystic Fibrosis Impact on Cellular Function Preeti Rao John Carroll University, prao14@jcu.edu
More informationDrug Use Criteria: Ivacaftor (Kalydeco ) and Lumacaftor/Ivacaftor (Orkambi )
Texas Vendor Program Use Criteria: (Kalydeco ) and Lumacaftor/ (Orkambi ) Publication History Developed: October 2012 Revised: December 2017; February 2016; June 2014. Notes: Information on indications
More informationCystic Fibrosis. Cystic Fibrosis. Cystic Fibrosis 5/01/2011 CYSTIC FIBROSIS OF THE PANCREAS AND ITS RELATION TO CELIAC DISEASE. D ANDERSEN.
1938 OF THE PANCREAS AND ITS RELATION TO CELIAC DISEASE. D ANDERSEN. American Journal Diseases Children. : The beginning May 1938: 49 cases 25 20 15 Nos of cases 10 5 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Age
More informationBTIG LLC Dane Leone, CFA (212) Source: SAPHIRA 1 Results (December 20th 2016), Ph2a open label trial of GLPG1837
Pre-clinical assay outcomes at Vertex have proven to be reliable markers for in vivo results, we expect the same from Galapagos: Outcomes from the EVOLVE and EXPAND studies have set a new bar for clinical
More informationMichael Wilschanski Pediatric Gastroenterology, Hadassah Medical Organization Jerusalem, Israel
Recurrent Acute Pancreatitis in Israeli, Children Michael Wilschanski Pediatric Gastroenterology, Hadassah Medical Organization Jerusalem, Israel ISPGHAN EILAT FEBRUARY RY 2013 Etiologies of recurrent/chronic
More information1 (a) State the maximum magnification that can be achieved by a light microscope and a transmission electron microscope.
1 (a) State the maximum magnification that can be achieved by a light microscope and a transmission electron microscope. Select your answers from the list below. 10x 40x 100x light microscope... x transmission
More informationGenetic diseases. - chromosomal disorders (aneuploidy) - mitochondrial inherited diseases (female lineage transmission)
Genetic diseases - chromosomal disorders (aneuploidy) - monogenic diseases (mendelian transmission) - mitochondrial inherited diseases (female lineage transmission) HOWEVER: interaction gene-environment
More informationA CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation A BS TR AC T
The new england journal of medicine established in 112 november 3, 2011 vol. 365 no. 1 A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation Bonnie W. Ramsey, M.D., Jane Davies, M.D.,
More informationCystic Fibrosis. Advances and Asian Perspective Dr AS Paul 13 October 06
Cystic Fibrosis Advances and Asian Perspective Dr AS Paul 13 October 06 Cystic Fibrosis An Overview Asian Perspective Advances Cystic Fibrosis An Overview Epidemiology and Pathogenesis Most common severe
More information