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Presentation on theme: "UNITA’ OPERATIVA DI PEDIATRIA"— Presentation transcript:

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
For this reason, the CF community led by the CF Foundation, continues to support a wide range of therapeutic approaches. Although all approaches are important, today’s presentation will only cover anti-infectives and anti-inflammatories.

3 How much CFTR is enough? CF Carriers Normal
Pancreatic Insufficient CF Pancreatic Sufficient Carriers Normal Scott showed you this figure yesterday, explaining that we now know from both natural history studies and initial clinical trials of CFTR modulations, that recovering at least 30% activity of the CFTR protein is associated with a significant impact on symptoms. Please remember this 30% activity threshold as we proceed today. ≈ 30% CFTR activity associated with symptom reduction Adapted from Accurso et al JCF 2013 in press

4 CF is Not One Genetic Disorder CFTR mutation classes
X Cl - Class IV conductance Class V quantity Cl - Cl - Cl - X Class I synthesis Class II maturation Class III regulation Normal Normal CFTR protein is trafficked to the surface and activated as a Cl- channel. We also know that there are over 1000 CF genetic mutations, most of which can be placed in functional classes shown here. The classes on the left (I, II, III) are associated with more severe disease, including pancreatic insufficiency and the right side (IV, V) with a milder disease. Every patient has 2 mutations and if one is mild, fortunately, it will dominate. ‘severe’ mutations ‘mild’ mutations pancreatic insufficiency pancreatic sufficiency Adapted from

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; O’Sullivan et al. Lancet 2009;373: Class I Class II Class V Class III Class IV Little to no CFTR Gating Some Conductance Normal CFTR quantity and function Because of this range of mutations, treatment approaches must be directed to specific functional classes. As shown on the left, in severe classes, reduced levels of CFTR reach the cell surface requiring small molecules – termed correctors -- to assist in proper transport and folding of the protein, milder mutations on the right reach the cell surface but need a potentiator to permit proper function of the salt channel. Severe mutations will require a potentiator in addition to a corrector. Treatment approaches Correctors Potentiators

6 Class I nonsense mutations
Readthrough compound Full-length protein Shortened protein The most prominent class remaining is Class I or nonsense mutations. Here the nascent protein is never made correctly and is stopped prematurely in the translational process. 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* A further evaluation of the inhaled antibiotic sub-group demonstrated a larger treatment effect in the group of subjects who were not receiving chronic inhaled antibiotics at baseline vs. those who were on inhaled antibiotics at baseline.  The graph on the left shows a 6.7% difference in relative change in % predicted FEV1 in the ataluren-treated group compared with placebo, with an unadjusted p-value of In contrast, the graph on the right shows that there is no difference between ataluren and placebo in the inhaled antibiotics group. In 2014, PTC is initiating an ataluren Phase 3 efficacy and safety trial in patients not receiving inhaled aminoglycosides See Abstract 193 *Nominal p-values

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

9 CFTR proteins with Class II mutations do not reach the cell surface
Cultured F508del/F508del-human bronchial epithelial cells Cl - Cl - Cl - Cl - Cl - Cl - cilia X F508del Class II mutation cytoplasmic F508del CFTR The Class II mutations are very important in reaching our goal. These severe mutations do not reach the cell surface as shown in the photomicrograph of a human bronchial epithelial cell (or HBE) with the green stippling in the cytoplasm. 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 Lumacaftor, a corrector, also discovered through HTS, and the first to reach Phase 3 testing, demonstrates successful trafficking of F508del CFTR to the surface in HBE cells as shown here. Please note that the green staining is now concentrated at the cell surface. nuclei untreated + lumacaftor Van Goor et al., PNAS 2011


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