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Le armi terapeutiche per il trattamento della Fibrosi Cistica: nuove acquisizioni UNITA OPERATIVA DI PEDIATRIA Centro Regionale per la diagnosi, la cura.

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Presentation on theme: "Le armi terapeutiche per il trattamento della Fibrosi Cistica: nuove acquisizioni UNITA OPERATIVA DI PEDIATRIA Centro Regionale per la diagnosi, la cura."— Presentation transcript:

1 Le armi terapeutiche per il trattamento della Fibrosi Cistica: nuove acquisizioni UNITA OPERATIVA DI PEDIATRIA Centro Regionale per la diagnosi, la cura e la riabilitazione della Fibrosi Cistica 09/11/2013 Donatello SALVATORE

2 cff.org clinicaltrials.gov CF Foundation: le linee di ricerca terapeutica

3 How much CFTR is enough? Carriers Adapted from Accurso et al JCF 2013 in press Normal CF Pancreatic Insufficient Pancreatic Sufficient 30% CFTR activity associated with symptom reduction

4 CF is Not One Genetic Disorder CFTR mutation classes Adapted from Cl - Normal X Class I synthesis X Class II maturation X Class III regulation X Cl - X Class IV conductance Cl - Class V quantity severe mutations pancreatic insufficiency mild mutations pancreatic sufficiency

5 So, there must be mutation specific treatment approaches Reduced Quantity Reduced Function MacDonald et al. Pediatr Drugs 2007;9:1-10; Zielenski. Respiration 2000;67:117-33; Welsh et al. Cystic fibrosis In: Valle et al, eds. OMMBID. McGraw-Hill Companies Inc;2004:part 21,chap 201; OSullivan et al. Lancet 2009;373: Class I Class II Class I Class II Class V Class III Class IV Little to no CFTR Little to no CFTR Gating Some CFTR Some CFTR Conductance Normal CFTR quantity and function CorrectorsPotentiators Treatment approaches

6 Class I nonsense mutations Adapted from Schmitz A, Famulok M. Nature 2007 Nonsense mutation Readthrough compound Shortened protein Full-length protein

7 Mean Relative Change in %-Predicted FEV 1 at Week 48 by Chronic Baseline Inhaled Antibiotic Use No Inhaled Antibiotics Week 48 = 6.7% p = 0.013* Week 48 = 0.0% p = 0.88* Any Inhaled Antibiotics *Nominal p-values See Abstract 193 In 2014, PTC is initiating an ataluren Phase 3 efficacy and safety trial in patients not receiving inhaled aminoglycosides

8 Therapeutic Approaches by Class F508del CFTR Processing Corrector Adapted from New Engl J Med 352(19): , 2005

9 cytoplasmic F508del CFTR Cultured F508del/F508del- human bronchial epithelial cells Van Goor et al., PNAS 2011 CFTR proteins with Class II mutations do not reach the cell surface Cl - Normal CFTR X F508del Class II mutation cilia nuclei

10 Van Goor et al., PNAS 2011 Lumacaftor increases the amount of F508del-CFTR at the cell surface Cultured F508del/F508del-human bronchial epithelial cells CFTR cilia nuclei untreated + lumacaftor


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