Post on 15-Mar-2018
Asthma and Cystic Fibrosis
Christopher Hug, MD, PhDDivision of Respiratory Diseases
Children’s Hospital Boston
Whitehead Institute
What is Asthma?
What is Cystic Fibrosis?
What can these conditions tell us about
lung biology and disease?
Case 1:
5 year old boy, born in Boston. Coughs and wheezes frequently.Several viral illnesses per year. First, and most severe episode,
occurred when he was 7 months old.Good growth and development.Has patches of dry skin on elbows and cheeks.Mother, father, and sister with similar symptoms.Father smokes, but “only outside.”Lives near Dudley MBTA station.
Case 2:
11 year old boy, born in Boston. Coughs and wheezes frequently, with bronchitis and pneumonias.Difficulty gaining weight; frequent constipation
and abdominal pain.Nasal polyps noted.Other family members healthy. Visits relatives in Ireland and
Scotland yearly.No smokers or environmental exposures.
Case 3:
19 year old woman, born in Boston. Coughs only occasionally, wheezes with exercise.Generally healthy, moderately overweight.Frequent loose stools.Mother morbidly obese; father healthy.Noted to have “lung scarring” on chest X-ray, taken by
Immigration Service when visiting family in Montreal.
Asthma:
intermittent obstruction to air flow induced by
a variety of stimuli in a susceptible individual.
Genetic: strong family history
Immunologic: inflammation
Environmental: irritants and allergens
Infectious: viral infections and inflammation
Mechanical: obstruction to airflow
Airway Inflammation in Childhood Asthma
Barbato, AJRCCM, 2003
Asthma Control
Thickening of basement membrane, leads to proliferation of smoothmuscle and reduced airway lumen.
What causes a reduction in airway lumen?-inflammation
infection, usually viralirritation, such as gastric acidallergic, autoimmunesystemic illness or disease
What causes a reduction in airway lumen?-inflammation
infection, usually viralirritation, such as gastric acidallergic, autoimmunesystemic illness or disease
Chronic airway inflammation and constrictionmay become irreversible with time, asthe lung responds to inflammation withproliferation of smooth muscle around the airway.
Why is constriction of the airways a bad thing?
Resistance to laminar flow within the connecting airways is dependent on several properties of the lung
(Poiseuille’s law)
R = 8 nl !r4
n viscosityl lengthr radius
Why is constriction of the airways a bad thing?
Resistance to laminar flow within the connecting airways is dependent on several properties of the lung
(Poiseuille’s law)
R = 8 nl !r4
n viscosityl lengthr radius
If the radius is halved, the resistance increases 16-fold!
How is asthma diagnosed?
-history: wheezes with colds-physical exam: wheeze, cough, signs of allergy-laboratory evaluation:
Chest X-rayPulmonary Function Tests (PFT)Peak Expiratory Flow Rate (PEFR)lab tests:
immune functionallergic componentsweat test (CF)
Asthma Severity Scoring
• Mild Intermittent
• Mild Persistent
• Moderate Persistent
• Severe Persistent
Control of Factors Contributing toAsthma Severity
• Allergens
• Environmental triggers
• Exercise
• Can asthma be prevented?
Pharmacologic Therapy
• Goals of therapy
• Step-wise approach to asthmamanagement
• Follow-up recommendations
Effects of InhaledCorticosteroids on Inflammation
Pre– and post–3-month treatment with budesonide (BUD) 600 mcgb.i.d.
Laitinen et al. J Allergy Clin Immunol. 1992;90:32-42.
E = Epithelium
BM = Basement Membrane
B cellB cell
IgEIgE
dendriticdendriticcellcell
ICAM-1/3ICAM-1/3
IL-1IL-1
CD4CD4
antigen presentationantigen presentation
IL-12IL-12
CD8CD8
mastmastcellcell
MCP-3MCP-3
IL-5IL-5
IL-6IL-6
NCFNCFMIP-1MIP-1αα
LTB-4LTB-4
SCFSCF
IL-3IL-3
IL-14IL-14
tryptasetryptase
GM-CSFGM-CSF
LTC-4LTC-4
RANTESRANTES
TNF-TNF-αα
IL-8IL-8
eotaxineotaxin
IL-13IL-13
LTE-4LTE-4
IFN-IFN-γγ
PGDPGD22histaminehistamine
IL-1IL-1
PAFPAF
chemokineschemokines
LTD-4LTD-4
IL-4IL-4
neuroneneurone
neurokininsneurokininsmyofibroblastmyofibroblast
GM-CSFGM-CSFC-kitC-kit
IL-6IL-6Th-2Th-2
SCFSCF
GM-CSFGM-CSF
IL-13IL-13
TNF-TNF-αα
IL-1IL-1αα
IgEIgEIL-10IL-10
IL-4IL-4
IL-3IL-3
IL-5IL-5
IL-6IL-6
Th-1Th-1TNF-TNF-ββ
IL-2IL-2
IFN-IFN-γγ
Th-0Th-0
GM-CSFGM-CSF
IL-2IL-2
IFN-IFN-γγ
IL-4IL-4
basophilbasophil
histaminehistaminecytokinescytokines
LTC-4LTC-4
LTD-4LTD-4
LTE-4LTE-4
IL-13IL-13
IL-4IL-4
PGSPGS
IgEIgEGM-CSFGM-CSF PAFPAF
proteaseprotease
IL-6IL-6 IL-8IL-8
neutrophilneutrophil
TNF-TNF-ααTGF-TGF-ββ11
PAFPAF
LTD-4LTD-4
TXATXA22
IL-1IL-1ββ
IL-6IL-6
MPOMPO
O speciesO speciesBIPBIP
IL-8IL-8
LTB-4LTB-4
LTC-4LTC-4
endothelial cellendothelial cell
adhesion moleculesadhesion molecules
GM-CSFGM-CSFICAM-1ICAM-1
IL-4IL-4
L-selectinL-selectinPGSPGS
TNF-TNF-αα
ET-2ET-2
ET-1ET-1
IL-1IL-1
G-CSFG-CSF IL-6IL-6
fibroblastfibroblast
TGF-TGF-ββ
PDGFPDGF
GM-CSFGM-CSFIL-1IL-1
IL-6IL-6
MIP-1MIP-1 RANTESRANTES
COLLAGEN I, II,COLLAGEN I, II,VV
IL-8IL-8
MCP-1MCP-1
PGEPGE22
collagenasecollagenase
ICAM-1ICAM-1 IL-11IL-11SCFSCF
VCAM-1VCAM-1
eosinophileosinophil
LTC-4LTC-4
MCP-3MCP-3
IL-4IL-4
IL-6IL-6
IL-10IL-10
LTD-4LTD-4
OO22
PDGF-BPDGF-B
ECPECP
IL-5IL-5
IL-8IL-8
HB-EGFHB-EGF
TGFTGF
GM-CSFGM-CSF
TXB-2TXB-2
RANTESRANTES
TNF-TNF-αα
IL-3IL-3
IL-1IL-1αα
EDPEDP
MBPMBP
15-HETE15-HETEIL-2IL-2
PAFPAF
0 species0 species
IFN-IFN-γγ
IL-1IL-133
MIP-1MIP-1αα
CR-3CR-3EDNEDN
ICAM-1ICAM-1
MCP-2MCP-2
MCP-1MCP-1
macrophagemacrophage
IL-IL-ββ
IL-5IL-5
MCP-3MCP-3
MIP-1MIP-1αα
iNOSiNOS
PAFPAF
IL-10IL-10
LTB-4LTB-4
EAFEAFIL-1IL-1ββ
TNF-TNF-αα
IL-6IL-6
IL-1IL-1
eotaxineotaxin
PGEPGE22
IL-12IL-12
IFN-IFN-γγ
RANTESRANTES
IL-3IL-3
GM-CSFGM-CSF
0 species0 species
IL-8IL-8proteaseprotease
epithelial cellepithelial cell
MCP-1MCP-1
IL-5IL-5
IL-3IL-3
15-LD15-LD
SLPISLPI
NEPNEP
COXCOX22
iNOSiNOS
15-LT515-LT5
PGFPGF22αα
PGEPGE22
IGF-IIGF-I
CGRPCGRP
FGFFGFIL-16IL-16
IL-8IL-8CPLACPLA22adhesion moleculesadhesion molecules
GRO-GRO-ββ
NONO
GM-CSFGM-CSF
MCP-2MCP-2
RANTESRANTES
IL-1IL-1ββ
TNF-TNF-αα
IL-6IL-6
IL-11IL-11
ET-1ET-1
VIPVIP
9/13 HODE9/13 HODE
15-HETE15-HETE
eotaxineotaxinIL-17IL-17PDGFPDGF
IL-10IL-10MIP-1MIP-1αα
ICAM-1ICAM-1
RANTESRANTES
smoothsmoothmuscle cellmuscle cell
cytokinescytokines
eotaxineotaxin
GM-CSFGM-CSF
IL-8IL-8
MCP-1MCP-1PGEPGE22
MCP-2MCP-2
MCP-3MCP-3
Mediator releasemodified
monocytemonocyte
IL-5IL-5
MCP-3MCP-3
MIP-1MIP-1αα
NONO
IL-1IL-1ββ
TNF-TNF-αα
eotaxineotaxin
PGEPGE22
IFN-IFN-γγ
RANTESRANTES
IL-3IL-3 GM-CSFGM-CSF
0 species0 species
IL-2IL-2
TXATXA22
IL-4IL-4
IL-8IL-8
cytokinescytokines
IL-6IL-6 IL-10IL-10IL-12IL-12
LTB-4LTB-4LTC-4LTC-4 ICAM-1ICAM-1
G-CSFG-CSF
IFN-IFN-γγ
Effects of Corticosteroids on Inflammatory Cells
B cellB cell
IgEIgE
dendriticdendriticcellcell
ICAM-1/3ICAM-1/3
IL-1IL-1
CD4CD4
antigen presentationantigen presentation
IL-12IL-12
CD8CD8
mastmastcellcell
MCP-3MCP-3
IL-5IL-5
IL-6IL-6
NCFNCFMIP-1MIP-1αα
LTB-4LTB-4
SCFSCF
IL-3IL-3
IL-14IL-14
tryptasetryptase
GM-CSFGM-CSF
LTC-4LTC-4
RANTESRANTES
TNF-TNF-αα
IL-8IL-8
eotaxineotaxin
IL-13IL-13
LTE-4LTE-4
IFN-IFN-γγ
PGDPGD22histaminehistamine
IL-1IL-1
PAFPAF
chemokineschemokines
LTD-4LTD-4
IL-4IL-4
neuroneneurone
neurokininsneurokininsmyofibroblastmyofibroblast
GM-CSFGM-CSFC-kitC-kit
IL-6IL-6Th-2Th-2
SCFSCF
GM-CSFGM-CSF
IL-13IL-13
TNF-TNF-αα
IL-1IL-1αα
IgEIgEIL-10IL-10
IL-4IL-4
IL-3IL-3
IL-5IL-5
IL-6IL-6
Th-1Th-1TNF-TNF-ββ
IL-2IL-2
IFN-IFN-γγ
Th-0Th-0
GM-CSFGM-CSF
IL-2IL-2
IFN-IFN-γγ
IL-4IL-4
basophilbasophil
histaminehistaminecytokinescytokines
LTC-4LTC-4
LTD-4LTD-4
LTE-4LTE-4
IL-13IL-13
IL-4IL-4
PGSPGS
IgEIgEGM-CSFGM-CSF PAFPAF
proteaseprotease
IL-6IL-6 IL-8IL-8
neutrophilneutrophil
TNF-TNF-αα
TGF-TGF-ββ11
PAFPAF
LTD-4LTD-4
TXATXA22
IL-1IL-1ββ
IL-6IL-6
MPOMPO
O speciesO speciesBIPBIP
IL-8IL-8
LTB-4LTB-4
LTC-4LTC-4
endothelial cellendothelial cell
adhesion moleculesadhesion molecules
GM-CSFGM-CSFICAM-1ICAM-1
IL-4IL-4
L-selectinL-selectinPGSPGS
TNF-TNF-αα
ET-2ET-2
ET-1ET-1
IL-1IL-1
G-CSFG-CSF IL-6IL-6
fibroblastfibroblast
TGF-TGF-ββ
PDGFPDGF
GM-CSFGM-CSFIL-1IL-1
IL-6IL-6
MIP-1MIP-1 RANTESRANTES
COLLAGEN I, II, VCOLLAGEN I, II, V
IL-8IL-8
MCP-1MCP-1
PGEPGE22
collagenasecollagenase
ICAM-1ICAM-1 IL-11IL-11
SCFSCF
VCAM-1VCAM-1
eosinophileosinophil
LTC-4LTC-4
MCP-3MCP-3
IL-4IL-4
IL-6IL-6
IL-10IL-10
LTD-4LTD-4
OO22
PDGF-BPDGF-B
ECPECP
IL-5IL-5
IL-8IL-8
HB-EGFHB-EGF
TGFTGF
GM-CSFGM-CSF
TXB-2TXB-2
RANTESRANTES
TNF-TNF-αα
IL-3IL-3
IL-1IL-1αα
EDPEDP
MBPMBP
15-HETE15-HETEIL-2IL-2
PAFPAF
0 species0 species
IFN-IFN-γγ
IL-13IL-13
MIP-1MIP-1αα
CR-3CR-3EDNEDN
ICAM-1ICAM-1
MCP-2MCP-2
MCP-1MCP-1
macrophagemacrophage
IL-IL-ββ
IL-5IL-5
MCP-3MCP-3
MIP-1MIP-1αα
iNOSiNOS
PAFPAF
IL-10IL-10
LTB-4LTB-4
EAFEAF
IL-1IL-1ββ
TNF-TNF-αα
IL-6IL-6
IL-1IL-1
eotaxineotaxin
PGEPGE22
IL-12IL-12
IFN-IFN-γγ
RANTESRANTES
IL-3IL-3
GM-CSFGM-CSF
0 species0 species
IL-8IL-8
proteaseprotease
epithelial cellepithelial cell
MCP-1MCP-1
IL-5IL-5IL-3IL-3
15-LD15-LD
SLPISLPI
NEPNEP
COXCOX22
iNOSiNOS
15-LT515-LT5
PGFPGF22αα
PGEPGE22
IGF-IIGF-I
CGRPCGRPFGFFGF
IL-16IL-16IL-8IL-8CPLACPLA22
adhesion moleculesadhesion moleculesGRO-GRO-ββ
NONO
GM-CSFGM-CSF
MCP-2MCP-2
RANTESRANTES
IL-1IL-1ββ
TNF-TNF-αα
IL-6IL-6
IL-11IL-11
ET-1ET-1
VIPVIP9/13 HODE9/13 HODE
15-HETE15-HETEeotaxineotaxin
IL-17IL-17PDGFPDGF
IL-10IL-10MIP-1MIP-1αα
ICAM-1ICAM-1
RANTESRANTES
smoothsmoothmuscle cellmuscle cell
cytokinescytokines
eotaxineotaxin
GM-CSFGM-CSF
IL-8IL-8
MCP-1MCP-1PGEPGE22
MCP-2MCP-2
MCP-3MCP-3
Mediator releasemodified
monocytemonocyte
IL-5IL-5
MCP-3MCP-3
MIP-1MIP-1αα
NONO
IL-1IL-1ββ
TNF-TNF-αα
eotaxineotaxin
PGEPGE22
IFN-IFN-γγ
RANTESRANTES
IL-3IL-3 GM-CSFGM-CSF
0 species0 species
IL-2IL-2
TXATXA22
IL-4IL-4
IL-8IL-8
cytokinescytokines
IL-6IL-6 IL-10IL-10 IL-12IL-12
LTB-4LTB-4LTC-4LTC-4 ICAM-1ICAM-1
G-CSFG-CSF
IFN-IFN-γγ
Effects of Leukotriene Modifiers onInflammatory Cells
Do children outgrow asthma?
MARTINEZ, JACI, 1999
Description of Cystic FibrosisDescription of Cystic Fibrosis““Cystic Fibrosis of the Pancreas and itsCystic Fibrosis of the Pancreas and its
Relation to Celiac Disease: A Clinical andRelation to Celiac Disease: A Clinical andPathologic StudyPathologic Study””
Dorothy H. Anderson, M.D.Dorothy H. Anderson, M.D.Am J Am J Dis Dis ChildChild 1938;56:344-99 1938;56:344-99
““The chief pathologic changes were asThe chief pathologic changes were asfollows:follows:
1. The 1. The acinar acinar tissue of the pancreas wastissue of the pancreas wasreplaced by epithelium-lined cystsreplaced by epithelium-lined cystscontaining concretionscontaining concretions……
2. The lungs showed bronchitis,2. The lungs showed bronchitis,bronchiectasis, pulmonary abscessesbronchiectasis, pulmonary abscessesarising in the bronchiarising in the bronchi…”…”
Cystic FibrosisCystic Fibrosisνν Most common lethal inherited disease in CaucasiansMost common lethal inherited disease in Caucasians
(25,000 in US)(25,000 in US)νν Incidence: 1:2500 births (4% carriers)Incidence: 1:2500 births (4% carriers)νν Clinical manifestations: progressive bronchiectasis, chronicClinical manifestations: progressive bronchiectasis, chronic
cough and sputum production, dyspnea, respiratory failurecough and sputum production, dyspnea, respiratory failureνν Standard therapy: chest physical therapy, inhaledStandard therapy: chest physical therapy, inhaled
mucolyticsmucolytics, antibiotics, and oral pancreatic enzyme, antibiotics, and oral pancreatic enzymereplacementreplacement
νν Median survival (years):Median survival (years):νν Enzyme supplementsEnzyme supplementsνν Improved antibioticsImproved antibioticsνν General care and nutritionGeneral care and nutrition
0
5
10
15
20
25
30
35
1940 1950 1960 1970 1980 1990 2000
Organs affected by CFOrgans affected by CF
νν AirwaysAirwaysνν LiverLiverνν PancreasPancreasνν Small intestineSmall intestineνν Reproductive tractReproductive tractνν Skin (sweat gland)Skin (sweat gland)
CFTR: Cystic Fibrosis Transmembrane Regulator
Gene cloned in 1989 by studying large families with CF
Located on chromosome 7, spanning 188,700 bp; 27 exons
Many mutations now identified: over 800 individual mutations that cause CF
“Hot-spot” for mutation - possible role in pathogenesis?
Most common in Northern Europe:delta-F 508 homozygous, caused by a triplet nucleotidedeletion
Localization of CFTR expressionLocalization of CFTR expressionEpithelial (high)Epithelial (high)
Pancreatic ductsPancreatic ductsSalivary/sweat ductsSalivary/sweat ducts
Male genital ductsMale genital ducts
Kidney tubulesKidney tubules
Epithelial (low)Epithelial (low)
LungLung
Jejunum/colonJejunum/colon
Potential otherPotential other
Fibroblasts, organellesFibroblasts, organelles
Respiratory epitheliumRespiratory epithelium
(Exocrine tissues)(Exocrine tissues)
Infection and inflammation leadInfection and inflammation leadto airway obstructionto airway obstruction
Correlates of pulmonary diseaseCorrelates of pulmonary diseaseprogression: Bronchiectasisprogression: Bronchiectasis
Pathogenesis of CF lung diseasePathogenesis of CF lung disease
Predicted structure of CFTRPredicted structure of CFTR(Cystic Fibrosis Transmembrane conductance(Cystic Fibrosis Transmembrane conductance
Regulator)Regulator)
CF pathophysiology: role ofCF pathophysiology: role ofCFTRCFTR
CF: a heterozygote advantage?CF: a heterozygote advantage?
νν Clinical picture of CF reported world-wideClinical picture of CF reported world-wideνν Highest gene frequency found in Northern EuropeHighest gene frequency found in Northern Europe
(approximately 1 in 25)(approximately 1 in 25)νν Persistence of a Persistence of a ““lethallethal”” gene: gene:
νν genetic driftgenetic driftνν recurrent random mutationsrecurrent random mutationsνν heterozygote advantage (increased fertility or survival benefit)heterozygote advantage (increased fertility or survival benefit)
νν Selective advantage of 2% occurring 23 generations agoSelective advantage of 2% occurring 23 generations agocould explain high observed incidence of CFcould explain high observed incidence of CF
Principal infectious causes ofPrincipal infectious causes ofinfant mortalityinfant mortality
(ca 500-1500 AD)(ca 500-1500 AD)
νν PlaguePlagueνν SmallpoxSmallpoxνν TyphusTyphusνν Endemic tuberculosisEndemic tuberculosisνν Epidemic choleraEpidemic cholera
Rodman and Zamudio, Med Hypoth 1991; 36:253
CF: a heterozygote advantageCF: a heterozygote advantage
Fluid accumulation in mouse small intestine in response to infusion of cholera toxin
0
0.5
1
1.5
2
-/- wt/- wt/wt
CFTR genotype
Flui
d ac
cum
ulat
ion
ratio
Gabriel et al, Science 1994, 266:107
CFTR genotype
Basic defect
Symptoms
Modifier genes
Environmentalfactors
Effectors of CFTR PhenotypeEffectors of CFTR Phenotype
CFTR Mutations in Other DiseasesCFTR Mutations in Other Diseasesνν Congenital bilateral absence of vas deferens (CBAVD)Congenital bilateral absence of vas deferens (CBAVD)
νν Obstructive Obstructive azoospermiaazoospermia
νν Chronic obstructive pulmonary disease (COPD)Chronic obstructive pulmonary disease (COPD)
νν Diffuse Diffuse bronchiectasisbronchiectasis
νν Allergic Allergic broncopulmonary aspergillosisbroncopulmonary aspergillosis
νν Chronic pseudomonas bronchitisChronic pseudomonas bronchitis
νν Chronic bronchial Chronic bronchial hypersecretionhypersecretion
νν Chronic sinusitisChronic sinusitis
νν PancreatitisPancreatitis
νν AsthmaAsthma
Genotype-Phenotype CorrelationsGenotype-Phenotype Correlations
Sweat gland:GOOD
Pancreas: GOOD
Lung: BAD
Genotype
Adapted from Welsh and Smith. Sci Am. 1995;273:52-59.
CFTR Mutation andCFTR Mutation andClinical ConsequenceClinical Consequence
Severity scale
CFNormal PS PI
Typical mutations
CBAVD,COPD,
pancreatitis,etc.
Atypical mutations
CF lung diseaseCF lung disease
Molecular Consequences of CFTRMolecular Consequences of CFTRMutationsMutations
Normal I II III IV V
NonsenseG542X
Frameshift394delTT
Splice junction1717-1G–>A
Missense MissenseG551D
MissenseR117H
AlternativeSplicing
3849+10kbC–>T
AA deletionΔF508
MissenseA455E
Nosynthesis
Block inprocessing
Alteredconductance
Block inregulation
Reducedsynthesis
Abnormal GeneAbnormal Gene Abnormal ProteinAbnormal Protein
Altered Ion TransportAltered Ion TransportAbnormal MucusAbnormal Mucus
SecretionSecretion
Infection &Infection &InflammationInflammation
Tissue DestructionTissue Destruction
Organ DestructionOrgan DestructionRespiratoryRespiratory
FailureFailure
New therapies for CFNew therapies for CF
Genetic therapyGenetic therapyGenetic therapyGenetic therapy- - tgAAVCFtgAAVCF- - LiposomesLiposomes- Receptor-mediated- Receptor-mediated Gene transfer Gene transfer
Molecular therapyMolecular therapy Ion TransportIon Transport- - INS37217INS37217- Moli1901- Moli1901 ( (DuramycinDuramycin))
InflammationInflammation
InfectionInfection- - TOBI efficacy studyTOBI efficacy study- TOBI nebulizer study- TOBI nebulizer study- P113D- P113D- IB367- IB367- RSV vaccines- RSV vaccines- PA1806- PA1806- Macrolides- Macrolides
MucolyticMucolytic- - NacystelynNacystelyn
-- GentamicinGentamicin-- PhenylbutyratePhenylbutyrate- - GenesteinGenestein- 7,8 - 7,8 BenzoflavonesBenzoflavones-- CPX CPX-- CurcuminCurcumin
OrganOrganTransplantationTransplantation
DestructionDestruction
Gene replacement therapyGene replacement therapy
νν Rationale: abnormal gene leads to production ofRationale: abnormal gene leads to production ofabnormal CFTRabnormal CFTR
νν Available therapies:Available therapies:νν nonenone
νν Potential therapies:Potential therapies:νν viral vectorsviral vectorsνν non-viral methodsnon-viral methods
CFTR molecular therapyCFTR molecular therapy
νν Rationale: abnormalities in CFTR lead to defective processing,Rationale: abnormalities in CFTR lead to defective processing,regulation, or conductionregulation, or conduction
νν Available therapies:Available therapies:νν nonenone
νν Potential therapies:Potential therapies:νν replace missing CFTR proteinreplace missing CFTR proteinνν ““chaperonechaperone”” CFTR to apical membrane (i.e. CFTR to apical membrane (i.e. ΔΔF508)F508)
νν activate defective CFTRactivate defective CFTRνν suppress stop-codon mutations with antibiotics, suchsuppress stop-codon mutations with antibiotics, such
as as gentamicingentamicin
Airway secretions and clearanceAirway secretions and clearance
PulmozymePulmozyme®® (rhDNase) (rhDNase)improves CF sputum pourabilityimproves CF sputum pourability
Shak S, et al Proc Natl Acad Sci USA 1990;87:9188-92
N-acetyl L-cysteine (N-acetyl L-cysteine (MucomystMucomyst))
νν MucolyticMucolytic
νν Anti-inflammatoryAnti-inflammatory
νν AntiproteaseAntiprotease
νν AntioxidantAntioxidant
TOBI: inhaled TOBI: inhaled tobramycintobramycinantibioticantibiotic
νν Specific and potent antibiotic againstSpecific and potent antibiotic againstpseudomonas bacteriapseudomonas bacteria
νν Inhaled delivery system reduces systemic toxicityInhaled delivery system reduces systemic toxicityνν Usually combined with other antibioticsUsually combined with other antibioticsνν Can be delivered at home, reducing exposureCan be delivered at home, reducing exposure
to other bacteriato other bacteria
Airway inflammation in CF:Airway inflammation in CF:Neutrophil dominatedNeutrophil dominated
Anti-Anti-inflammatory inflammatory therapy: Effecttherapy: Effectof ibuprofen on FEV1of ibuprofen on FEV1
Konstan MW, et al New Eng J Med 1995;332:848-854
Lung TransplantationLung Transplantation
νν Final therapeutic optionFinal therapeutic optionνν Technical and surgical hurdles manageableTechnical and surgical hurdles manageableνν Decision when to transplant remains difficultDecision when to transplant remains difficultνν 5-year survival is approximately 50%5-year survival is approximately 50%νν Limited availability of organ donationLimited availability of organ donationνν Challenge is in long term treatment of immuno-Challenge is in long term treatment of immuno-
suppression and rejectionsuppression and rejection
Abnormal GeneAbnormal Gene Abnormal ProteinAbnormal Protein
Altered Ion TransportAltered Ion TransportAbnormal MucusAbnormal Mucus
SecretionSecretion
Infection &Infection &InflammationInflammation
Tissue DestructionTissue Destruction
Organ DestructionOrgan DestructionRespiratoryRespiratory
FailureFailure
TransplantationTransplantation
Acute andAcute andchronic rejectionchronic rejection
Long termLong termimmmuno-immmuno-supressionsupression
Genetic therapyGenetic therapy Molecular therapyMolecular therapy Ion TransportIon Transport
InflammationInflammation
InfectionInfection- - tgAAVCFtgAAVCF**- - LiposomesLiposomes- Receptor-mediated- Receptor-mediated Gene transfer Gene transfer
- INS37217*- INS37217*- Moli1901- Moli1901 ( (DuramycinDuramycin))
Therapeutic Approaches to CFTherapeutic Approaches to CF
- TOBI efficacy study*- TOBI efficacy study*- TOBI nebulizer study- TOBI nebulizer study- P113D- P113D- IB367- IB367- RSV vaccines- RSV vaccines- PA1806- PA1806- Macrolides- Macrolides
- DHA (- DHA (LumarelLumarel))- - Protease inhibitorsProtease inhibitors- BIIL 284*- BIIL 284*- - TyloxapolTyloxapol- GSH, - GSH, ImmunocalImmunocal- Interferon gamma- Interferon gamma
MucolyticMucolytic- - NacystelynNacystelyn**
-- GentamicinGentamicin-- PhenylbutyratePhenylbutyrate- - GenesteinGenestein- 7,8 - 7,8 BenzoflavonesBenzoflavones-- CPX CPX-- CurcuminCurcumin**
Future Studies and TreatmentsFuture Studies and Treatments
νν Improved nutrition, antibiotics, and supportImproved nutrition, antibiotics, and supportνν Role of early diagnosis through newbornRole of early diagnosis through newborn
screenscreenνν Gene therapyGene therapyνν Stem cell therapyStem cell therapyνν Improved transplantation treatmentsImproved transplantation treatmentsνν Modifying genesModifying genesνν Understanding of cellular role of CFTRUnderstanding of cellular role of CFTR
proteinprotein
What do Asthma and CF have inWhat do Asthma and CF have incommon?common?
νν Genetic basisGenetic basisνν Broad spectrum of clinical presentationBroad spectrum of clinical presentationνν Expression of symptoms related to otherExpression of symptoms related to other
factorsfactorsνν Airway inflammationAirway inflammationνν Similar treatments: anti-inflammatorySimilar treatments: anti-inflammatory
medicationsmedicationsνν Modifying genesModifying genes
How do Asthma and CF differ?How do Asthma and CF differ?
νν Genetic basis: single gene versus manyGenetic basis: single gene versus manyνν Tissue and organs affectedTissue and organs affectedνν Airway inflammationAirway inflammationνν Different treatments: antibiotics and nutritionDifferent treatments: antibiotics and nutritionνν Different progression of diseaseDifferent progression of diseaseνν Modifying genesModifying genes
νν However, basic science advances may shed light onHowever, basic science advances may shed light onboth diseasesboth diseases
AcknowledgementsAcknowledgements
Much of the material contained on the slides was provided bythe Cystic Fibrosis Foundation
Dr. Harvey F. LodishWhitehead Insitute
Drs. David Waltz and Greg SawickiChildren’s Hospital Boston
Special thanks to the patients for participating in clinical trials
BALF neutrophil counts in CFBALF neutrophil counts in CF
Birrer P, et al. Am J Resp Crit Care Med 1994;150:207-213
Molecular therapies for CFMolecular therapies for CF
Therapeutic approaches to CFTherapeutic approaches to CFlung diseaselung disease
Introduction to CysticIntroduction to CysticFibrosisFibrosis
Christopher Hug, MD, PhDChristopher Hug, MD, PhD
Pulmonary DivisionPulmonary Division
Department of MedicineDepartment of Medicine
ChildrenChildren’’s Hospital, Bostons Hospital, Boston