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
cff.org
clinicaltrials.gov
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
CF is Not One Genetic Disorder
CFTR mutation classes
Cl -
Cl -
Cl -
Cl -
Cl -
Cl -
Cl -
X
XX
Class III
regulation
Class IV
conductance
Cl -
Cl -
X
X
Normal
Cl -
Class I
synthesis
Class II
maturation
Class V
quantity
‘severe’ mutations
‘mild’ mutations
pancreatic insufficiency
pancreatic sufficiency
Adapted from http://www.umd.be/CFTR/W_CFTR/gene.html
So, there must be mutation specific
treatment approaches
Reduced Quantity
Normal CFTR
quantity and
function
Treatment
approaches
Little to no
CFTR
Some
CFTR
Class I
Class II
Class V
Correctors
Reduced Function
Gating
Class III
Conductance
Class IV
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
Class I nonsense mutations
Nonsense mutation
Readthrough
compound
Shortened protein
Adapted from Schmitz A, Famulok M. Nature 2007
Full-length protein
Mean Relative Change in %-Predicted FEV1 at Week 48
by Chronic Baseline Inhaled Antibiotic Use
No Inhaled Antibiotics
Any Inhaled Antibiotics
Change in %-Predicted FEV 1, Mean
Week 48 ∆ = 6.7%
p = 0.013*
Week 48 ∆ = 0.0%
p = 0.88*
6
6
Ataluren (N=52)
Placebo (N=53)
4
Ataluren (N=64)
Placebo (N=63)
4
2
2
0
-0.2%
0
-2
-2
 = 6.7%
-4
-4
-4.4%
-4.4%
-6
-6
-6.9%
-8
-8
BL
8
16
24
32
40
48
BL
8
16
24
32
40
48
Time, weeks
Time, weeks
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
Therapeutic Approaches by Class
F508del CFTR
Processing Corrector
Adapted from New Engl J Med 352(19): 1992-2001, 2005
CFTR proteins with Class II mutations
do not reach the cell surface
Cl -
Cl -
Cl -
Cl -
Cultured F508del/F508delhuman bronchial epithelial cells
Cl -
Cl -
cilia
X
Normal
CFTR
F508del
Class II mutation
Van Goor et al., PNAS 2011
cytoplasmic
F508del CFTR
nuclei
Lumacaftor increases the amount of
F508del-CFTR at the cell surface
Cultured F508del/F508del-human
bronchial epithelial cells
cilia
CFTR
nuclei
untreated
Van Goor et al., PNAS 2011
+ lumacaftor