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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 e la riabilitazione della Fibrosi Cistica. Le armi terapeutiche per il trattamento della Fibrosi Cistica: nuove acquisizioni. 09/11/2013. Donatello SALVATORE. CF Foundation: le linee di ricerca terapeutica.

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Le armi terapeutiche per il trattamento della Fibrosi Cistica: nuove acquisizioni

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

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

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

  4. CF is Not One Genetic DisorderCFTR mutation classes Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- X X X X X Normal Class I synthesis Class II maturation Class III regulation Class IV conductance Class V quantity ‘severe’ mutations ‘mild’ mutations pancreatic insufficiency pancreatic sufficiency Adapted from http://www.umd.be/CFTR/W_CFTR/gene.html

  5. So, there must be mutation specific treatment approaches Reduced Quantity Reduced Function Normal CFTR quantity and function Little to no CFTR Some CFTR Gating Conductance Class I Class II Class III Class IV Class V Treatment approaches Correctors Potentiators 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; O’Sullivan et al. Lancet 2009;373:1891-1904

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

  7. Mean Relative Change in %-Predicted FEV1 at Week 48 by Chronic Baseline Inhaled Antibiotic Use No Inhaled Antibiotics Any Inhaled Antibiotics Week 48 ∆ = 6.7% p = 0.013* Week 48 ∆ = 0.0% p = 0.88* In 2014, PTC is initiating an ataluren Phase 3 efficacy and safety trial in patients not receiving inhaled aminoglycosides *Nominal p-values See Abstract 193

  8. Therapeutic Approaches by Class F508del CFTR Processing Corrector Adapted from New Engl J Med 352(19): 1992-2001, 2005

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

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

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