A Quick Guide to the. CFTRdele2,3. Mutation CFTR SCIENCE

Transcription

1 Quick uide to the FRdele2,3 Mutation FR SIENE 2016 Vertex Pharmaceuticals Incorporated VXR-HQ a(1) 03/2016

2 Loss of FR activity is the underlying cause of cystic fibrosis (F) 1 Spectrum of Phenotypes ssociated With otal FR ctivity 1,2 otal FR ctivity % of Normal 100% No F Disease FR-related Disorders Some FR mutations result in residual or partial FR activity 3-5 0% 100% Some FR mutations result in little to no FR activity 3-5 0% 100% People with 2 FR mutations resulting in loss of FR activity generally have a F phenotype, which may include 1-3,6 Elevated sweat chloride (>60 mmol/l) Pancreatic insufficiency BVD a Lung function decline over time Pseudomonas aeruginosa colonization 0% ystic Fibrosis otal FR ctivity otal FR ctivity a BVD, congenital bilateral absence of the vas deferens. References: 1. Davis PB et al. m J Respir rit are Med. 1996;154(5): Rowe SM et al. Proc m horac Soc. 2007;4(4): Zielenski J. Respiration. 2000;67(2): Sheppard DN et al. Nature. 1993;362(6416): Welsh MJ, Smith E. ell. 1993;73(7): astellani et al. J yst Fibros. 2008;7(3):

3 Levels of FR activity affect survival in F 1 Survival Probability Survival urves by FR ctivity During a 10-Year Follow-Up ( ) of Patients From the US FF Registry a Residual FR activity (lass IV, V): R117H, R334W, R347P, Kb, , 455E Severely reduced FR activity (lass I, II, III): 542X, R553X, W1282X, R1162X, 621-I, , 1078del, 3659del, I507del, N1303K, S549N, 85E, F508del, 551D, R Risk ime (ge) n=1126 n=14, dapted with permission from McKone EF et al. hest. 2006;130(5): his survival curve represents population-based outcomes. 1 Individual outcomes in cystic fibrosis are variable. a Data are from a retrospective study of patients enrolled in the ystic Fibrosis Foundation patient registry measuring risk of death over a 10-year observation period from 1993 to Patients were grouped as having a high-risk or low-risk genotype based on the functional effects of their class of FR mutation on phenotype and mortality. Patients having a lass I, II, or III mutation on both alleles were considered high-risk, while patients having at least 1 lass IV or V mutation were categorized as low-risk. total of 15,651 patients had a FR genotype of a known functional class; 14,525 (93%) had a high-risk FR genotype and 1126 (7%) had a low-risk FR genotype.1 References: 1. McKone EF et al. hest. 2006;130(5): he World Bank. ccessed November 12, Dörk et al. Hum enet. 2000;106(3): Stanke F et al. J Med enet. 2008;45(1): Zielenski J. Respiration. 2000;67(2): Welsh MJ, Smith E. ell. 1993;73(7): MacKenzie et al. nn Int Med. 2014;161: Life expectancy in Western countries (general population born in 2000) is ~79 years 2 Between 1993 and 2002, median survival for US patients with genotypes associated with little to no FR activity was 36.3 years (95% I, 35.5 to 37.6 years), while median survival for those having genotypes associated with residual FR activity was 50 years (95% I, 47.1 to 55.9 years) 1 No patients with the FRdele2,3 mutation were included in this US registry study. FRdele2,3 is a lass I mutation, resulting in severely reduced FR activity 1,3-6 More recent US data ( ) suggest median survival across genotypes continues to improve 7 3

4 Only the Belgian country registry reports any prevalence of the FRdele2,3 mutation among patients with F1 Prevalence of the FRdele2,3 Mutation in Patients With ystic Fibrosis (% of Patients With at Least 1 llele) I n the FR2 global database, ~0.5% of patients with F have at least 1 copy of the FRdele2,3 mutation2 FRdele2,3 is prevalent among patients with F of Slavic descent3,4 dditional sources report frequency of the FRdele2,3 mutation on F alleles ountry zech Republic5 6% Russia5 5% Belarus 3% Lithuania5 2% Poland 2% anada6 0.1% 5 Belgium : 0.3% 1 5 References: 1. Belgisch Mucoviscidose Register Registre Belge de la Mucoviscidose. he Belgian ystic Fibrosis Registry. Summary Report ; Institute of Public Health (WIV-ISP), Brussels, Belgium. 2. US F Foundation, Johns Hopkins University, he Hospital for Sick hildren. he linical and Functional Ranslation of FR (FR2). ccessed November 12, Dörk et al. Hum enet. 2000;106(3): astellani et al. J yst Fibros. 2008;7(3): Bobadilla JL et al. Hum Mutat. 2002;19: World Health Organization. he molecular genetic epidemiology of cystic fibrosis: report of a joint meeting of WHO/EFN/IF(M)/EFS; June 19, 2002; enoa, Italy. World Health Organization; % of lleles 4

5 he FRdele2,3 mutation results in defective biosynthesis of the FR protein 1-4 FR urnover FR Function FR rafficking FR Processing Illustrative Example of lass I Defect olgi complex Endoplasmic reticulum Proteosome FR gene (DN) Rest of FR gene U U U Start codon Premature stop codon Rest of mrn strand mrn strand FRdele2,3 is a frameshift mutation, which produces a premature stop codon 1-3 he cell cannot synthesize a full-length FR protein, a lass I mutation 2,3 s a result, few to no FR proteins are present at the apical cell surface 2-4 mrn FR Synthesis ranscription DN References: 1. Dörk et al. Hum enet. 2000;106(3): Zielenski J. Respiration. 2000;67(2): Welsh MJ, Smith E. ell. 1993;73(7): Stanke F et al. J Med enet. 2008;45(1):

6 he FRdele2,3 allele results in little to no total FR activity otal FR activity can be defined as total ion transport mediated by FR protein channels at the cell surface, depending on FR protein quantity and function. 5 FR Quantity FRdele2,3 allele results in few to no FR channels at apical surface Defective Synthesis (lass I) x x hannel-open Probability hannel-open Probability: N/ FR Function x x 2 onductance onductance: N/ = = otal FR ctivity Little to No FRdele2,3 FR ctivity 3 1 virtual absence of FRdele2,3-FR protein quantity 2 regardless of function since few to no FR proteins reach the surface 3 results in little to no total FR activity N/, not applicable. References: 1. Dörk et al. Hum enet. 2000;106(3): Stanke F et al. J Med enet. 2008;45(1): Zielenski J. Respiration. 2000;67(2): Welsh MJ, Smith E. ell. 1993;73(7): Sheppard DN et al. Nature. 1993;362(3):

7 Both FR alleles play a role in determining phenotype or disease severity % No F Disease Normal individuals and F carriers otal FR ctivity FR-related Disorder linical entities associated with FR dysfunction that do not fulfill diagnostic criteria for F ystic Fibrosis FRdele2,3 allele results in little to no FR activity. he phenotype of a particular patient is also influenced by the mutation on the other allele 1,2,4-7 FRdele2,3 typically results in the indicated phenotypes 0% llele 1 otal FR ctivity Normal Normal Normal Residual Residual Little to None llele 2 otal FR ctivity Normal Residual Little to None Residual Little to None Little to None dapted from Zielenski J.Respiration. 2000;67(2): References: 1. US F Foundation, Johns Hopkins University, he Hospital for Sick hildren. he linical and Functional Ranslation of FR (FR2). ccessed November 12, deracia J et al. horax. 2005;60(7): ystic Fibrosis enotype-phenotype onsortium. N Engl J Med. 1993;329(18): Davis PB et al. m J Respir rit are Med. 1996;154(5): astellani et al. J yst Fibros. 2008;7(3): Zielenski J. Respiration. 2000;67(2): Dörk et al. Hum enet. 2000;106(3):

8 FRdele2,3 in combination with another allele that produces little to no FR activity usually results in a F phenotype 1-4 FR enotype llele #1: FRdele2,3 Little to No FR Protein ctivity llele #2 Little to No FR Protein ctivity F Phenotype In patients registered in the FR2 database with a FRdele2,3 mutation on 1 allele and a pancreatic insufficient mutation on the second allele 1 Modifier enes Little to No otal FR ctivity Environmental Factors Elevated sweat chloride (average): 99 mmol/l Lung function decline over time Pseudomonas colonization: 43% of patients Pancreatic insufficiency: 99% of patients References: 1. US F Foundation, Johns Hopkins University, he Hospital for Sick hildren. he linical and Functional Ranslation of FR (FR2). ccessed November 12, deracia J et al. horax. 2005;60(7): Davis PB et al. m J Respir rit are Med. 1996;154(5): astellani et al. J yst Fibros. 2008;7(3):

9 Summary Loss of FR activity is the underlying cause of F Levels of FR activity affect survival in F Only the Belgian country registry reports any prevalence of the FRdele2,3 mutation among patients with F he FRdele2,3 mutation results in defective biosynthesis of the FR protein he FRdele2,3 allele results in little to no total FR activity Both FR alleles play a role in determining phenotype or disease severity FRdele2,3 in combination with another allele that produces little to no FR activity usually results in a F phenotype 9