New treatments for cystic fibrosis: Where do we are?

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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

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