WEBCAST
PATRICK SOSNAY, MD Assistant Professor of Medicine Division of Pulmonary & Critical Care Medicine McKusick-Nathans Institute for Genetic Medicine Johns Hopkins Cystic Fibrosis Center Johns Hopkins University
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LEARNING OBJECTIVES • Explain how new CFTR modification advances point to changes that have to be made in clinical practice. • Describe the utility of genotype/phenotype correlations beyond diagnosis in achieving more effective patient treatment. • Integrate the patient into an individualized therapy regimen to improve outcomes.
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FULL DISCLOSURE POLICY AFFECTING THE JOHNS HOPKINS UNIVERSITY ACTIVITIES The following relationships have been reported for this activity: PLANNERS Faculty Relationship Michael Boyle, MD Scientific Advisory Board: Genentech, Inc., Vertex Pharmaceuticals, Incorporated, Gilead Sciences, and Savara Pharmaceuticals Principal Investigator: Vertex Pharmaceuticals, Incorporated No other planners have indicated that they have any financial interest or relationships with a commercial entity.
ACKNOWLEDGEMENTS
EDUCATIONAL SUPPORT • This activity is supported by an educational grant from Vertex to Johns Hopkins University School of Medicine. • All activity content and materials have been developed solely by the Johns Hopkins activity directors, planning committee members and faculty presenters, and are free of influence from Vertex.
YESTERDAY - OVERVIEW OF MUTATION CLASSES
LEARNING OBJECTIVES • Describe how CFTR mutations can be classified (by type, by class, by therapies). • Discuss the variety of CFTR mutations.
…IN 1989 www.theatlantic.com www.npr.org lifesciencesfoundation.org
CFTR MUTATION CLASSES Class I: Defective protein production with premature termination of CFTR production. Examples: G542X, 1717-1G->A, CFTRdele2,3. No protein produced . Class II: Defective processing or trafficking of CFTR. Examples: F508del, N1303K. No protein at the cell surface . Class III: Defective regulation of CFTR. Examples: G551D, S549N. Adequate protein, no CFTR activity . Class IV: CFTR chloride transport through the channel is defective. Examples: R117H, D1152H. Adequate protein, reduced CFTR activity . Class V: Reduced amount of functional CFTR. Examples: 2789+5G->A, 3849+10kbC->T. Reduced protein at cell surface . Class VI: Increased turnover, Reduced protein at cell surface . hopkinscf.org
PROBLEMS WITH CFTR MUTATION CLASSES • The class of most of the ~2000 CFTR mutations is not known – It can be implied based on mutation type (for nonsense “X” mutations, mutations to splice donor/acceptor sites “-1 or +1”, or mutations that cause a frameshift) – Unknown for missense mutations • Class is not always a simple assignment
CHANGE TO HGVS NOMENCLATURE Old “Legacy” HGVS name (by HGVS name (by Name nucleotide) protein) F508del c.1521_1523delCTT p.Phe508del G551D c.1652G>A p.Gly551Asp 3849+10kbC->T c.3717+12191C>T no protein name CFTRdele2,3 c.54-5940_273+10250del21kb p.Ser18ArgfsX16 Description: http://www.hgvs.org/mutnomen/; Taschner PEM, den Dunnen JT. Hum. Mutat. 2011 Translators available on: http://cftr2.org/index.php, http://www.genet.sickkids.on.ca/app
RESIDUAL FUNCTION: YES/NO? Discovery Magazine, June 2013
J Stuart Elborn, MD Professor, School of Medicine Dentistry and Biomedical Sciences Dean, School of Medicine Dentistry and Biomedical Sciences Centre for Infection and Immunity Queen’s University Belfast, Ireland FINANCIAL DISCLOSURES CONSULTANT: Vertex Incorporated, Novartis RESEARCH FUNDING: Vertex Incorporated, Novartis
TODAY- Ivacaftor and Beyond Small Molecule Therapy for Cystic Fibrosis Off-Label Discussion lumacaftor, ivacaftor, and ataluren
LEARNING OBJECTIVES • Describe how modulating and potentiating CFTR improves clinically important outcomes in CF. • Describe indication for potentiator and combination therapy in CF.
PERSONALIZED/STRATIFIED/PRECISION MEDICINE FOR CYSTIC FIBROSIS
IMPROVED SURVIVAL WITH TREATMENT INNOVATION Advances in therapy have been incremental Individual benefit is modest but cumulative – Stratified/Precision Life expectancy greatly increased Medicine for CF RCTs – Ivacaftor Mist Colistin DPI 40 tents CF gene Mannitol NPD and identified 35 Cl transport TIP Neonatal Aztreonam Airways 30 screening Clearance HTS 25 Azithromycin 1st successful Centre care Age (years) Sweat chloride Inhaled tobramycin pregnancy 20 test developed rhDNase 15 Inhaled colistin Discovery of high salt Antipseudomonal antibiotics 10 in sweat Antistaphylococcal antibiotics 1st pathologic Airway clearance 5 description Pancreatic Enzymes 0
CF AIRWAY DISEASE: PATHOPHYSIOLOGY Normal CF
WHAT IS STRATIFIED/PRECISION MEDICINE? • Patients respond differently, and these responses can be organized into groups Mark R. Trusheim, Ernst R. Berndt & Frank L. Douglas Nature Reviews Drug Discovery 6, 287-293 (April 2007)
CHALLENGES FOR STRATIFIED MEDICINE IN CF • Over 1900 CFTR mutations identified that result in a range of disease severity to no disease • Range in disease severity among people with the same CFTR mutations Modifier genes • Environment • • Stage of disease at time of treatment
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