TINTE PENTRU TINTE PENTRU
TRATAMENTUL TRATAMENTUL
PERSONALIZAT IN PERSONALIZAT IN
AFECTIUNILE INDUSE AFECTIUNILE INDUSE
DE MECANISMUL DE MECANISMUL
Th2/IgETh2/IgE
Diana DeleanuDiana Deleanu
ConflictConflicte dee de InterestInterest
• Niciunul
Afectiuni induse de mecanismul Afectiuni induse de mecanismul
Th2/IgETh2/IgE
DIANA DELEANUDIANA DELEANU
UMF Iuliu HatieganuUMF Iuliu Hatieganu
Inst Reg de GastroInst Reg de Gastro--Enterol si HepatolEnterol si Hepatol
AlergologieAlergologie
4
HYPERSENSITIVITY
IMMEDIATE DELAYED
TYPE I
Ig E - mediated
TYPE II
Cytotoxic
TYPE III
Immune Complex
TYPE IV
Cellular
ClasificareaClasificarea dupadupa P.Gell, P.Gell,
R.CoombsR.Coombs bazata pe bazata pe
mecanismulmecanismul patogenic. patogenic.
Rought (in 1980)Rought (in 1980)
tipul Vtipul V-- stimularestimulare
II –– IgEIgE, ,
II, IIIII, III –– IgM, G,IgM, G,
IVIV –– TT--effectorseffectors, ,
VV -- IgM, GIgM, G
Allergicreaction
IL-4
IL-5
Eosinophil
IgE
B
T
T
Th2
APC
Alergen
T
Th1
IFN-γ BIgG
IL-12 ↑
IL-12 ↓
RaspunsulRaspunsul Th1/Th2Th1/Th2
APC
ALERGENI
Th1
Th2
Eos
IL-5
BIL-4
Y
Y Y Y
Y Y IgE
MASTFibro
IL-13
MEDIATORI
ALERGENI
ECPEDXMBP
CD4 ITS
II-12
FAZAPRECOCE
HistaminaLTs
MOLECULEde ADEZIUNE
FAZA TARDIVA AINFLAMATIEI
REMODELARE
ADJUVANTI
RECRUTAREAENDOTHELINSiNOS
Neu
CELULELOR
Reactia alergica
7
Mecanismul Imunologic al Bolilor AlergiceMecanismul Imunologic al Bolilor Alergice
Fenomene ulterioare Expunerii la Alergen:Reactii Alergice Imediate, Tardive si
Hiperreactivitate
minute 1 2 3 4 5 6 7 8 9 10 -ore//------zile
Timpul dupa Contactul cu Alergenul
Symptome NazaleHiperreactivitatea
NazalaFazaImediata
FazaTardiva
Alergen
MecanismMecanismul ul reactiilor reactiilor
IgEIgE––mediatemediate
TTiippulul II de Hipersensibilitatede Hipersensibilitate –– AlergAlergia ia
Alergen IgE legat de suprafata mastocitelor
Degranularea, eliberarea
mediatorilori
+
Boli alergice Boli alergice
RinitaRinita ConjunctivitaConjunctivita Astm Dermatita atopica
Urticarie/angioedemDermatita de contactAlergie alimentara Soc anafilactic
An
nu
al
co
st
/ p
ati
en
t ($
)
Heart Disease
AllergyArthritis AsthmaAny Cancer
Mental Illness†
Diabetes Migraine / Headache
Resp. Infec.
0
50
100
150
200
250
300
350
400
450Inpatient OutpatientER RxAbsence STD
Presenteeism
*Assuming a $23.15/hour wage estimate†Depression, sadness, mental illness
HTN: hypertension; Resp.: respiratory; STD: short-term disability
Goetzel RZ. J Occup Environ Med. 2004;46:398-412.
Allergy is the 5th Most Costly Physical and Mental Health Condition
HTN
12
Impactul Alergiilor Impactul Alergiilor
asupra vietii pacientilorasupra vietii pacientilor
Not sure
1%
Didn't really impact
14%
Little
19%
Some
26%
A lot
15%
Moderate
25%
Q31. During allergy season, would you say the condition impacted your daily life …..? N=2,500
Tinte in bolile alergice Tinte in bolile alergice
(mediate prin Th2/IgE)(mediate prin Th2/IgE)
DIANA DELEANUDIANA DELEANU
UMF Iuliu HatieganuUMF Iuliu Hatieganu
Inst Inst RegReg de de GastroGastro--Enterol Enterol si si HepatolHepatol
AlergologieAlergologie
DefinitieDefinitie
•• MMedicinedicina a PersonalizPersonalizataata, uneori numita medicinmedicinaa
preciprecisa sa (exacta) sau individualizindividualizataata este un teren
in dezvoltare al medicinii care foloseste metode
de diagnostic ce identifica markeri biologicali
specifici, frecvent genetici, pentru a ajuta la
evaluarea tratamentului medical si a procedurilor
care au cea mai mare eficienta pentru fiecare
pacient in parte.
Nimeni nu este la felNimeni nu este la fel
Rol in
Diagnostic Salveaza Vieti
Tratament Salveaza Bani
Medicina PersonalizataMedicina Personalizata(precisa sau individuala)
Medicina personalizataMedicina personalizata
G. Passalacqua, GW Canonica. AIT (allergen immunotherapy): a model for the “precision medicine” �Clin Mol Allergy (2015) 13:24
IstoriaIstoria……diagnosticului diagnosticului
alergiiloralergiilor
1880 1995-991988-911967 2000 2008
Provocation tests (SPT)
First allergens cloned
RAST
Characterization & designation of IgE
Recombinant allergen panels recreating allergen extracts
First allergen microarray
ImmunoCAP ISAC (Phadia/ VBC Genomics)
IN-VITRO testing
IN-VIVO testing
Component – Resolved -Diagnostics
Standardization of allergen extracts
Dezvoltarea Patogenezie Dezvoltarea Patogenezie
si terapie in astmsi terapie in astm
Perioada Tinta terapeutica Medicatie
1960 Ameliora bronhospasmul SABA
1970 Preveni bronhospasmul Slbutamol, Teofilina
1980 Prevenirea bronhospasmului indus alergic Cromolin
1990 Preveni si rezolva inflamatia Corticosteroizi inhalatori
Modificatorii de leucotriene
LABA
Terapie combinata
2000 Controlul astmului Anti-IgE
2010 Medicina personalizata
Interventie precoce
preventie
Caracteristicile pacientului,
biomarkeri, genetica,
imunomodulatoare
Fig 1
Journal of Allergy and Clinical Immunology 2014 133, 16-26DOI: (10.1016/j.jaci.2013.10.040)
Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions
Medicina personalizataMedicina personalizata
Fig 4
Journal of Allergy and Clinical Immunology 2014 133, 16-26DOI: (10.1016/j.jaci.2013.10.040)
Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions
Medicina personalizataMedicina personalizata
IstoricIstoric
• In 4 I.C. Medicul grec
Hippocrates (460BC-370 IC)
a observat ca anumite alimente ,inofensive pentru majoritatea pot produce la unii imbolnavire.
„ Este mult mai important sa stim omul care are o boala decit sa stim boala pe care o are omul. ”
AlergeniiAlergenii
De interior si de exterior (+ autoalergeni)
CARACTERISTICI Der pDer p Der fDer f
dimensiuni 250-350 µ (0,2-0,3 mm) 310-390 µ
greutate 3,1 µg 3,4 µg
ciclu de viata ou, larva, ou, larva, protonimfa,
tritonimfa si adult tritonimfa si adult-in 20 zile la 25°C 30 zile, la 25°C
durata de viata 60-120 zile 100-120 zile
AlergenAlergen
• Major: Enzima (proteaza a tract digestiv, ce persista in fecale): Der p 1 (0.2 ng) Cysteine proteaza
• Minori: din exoschelet
• Der p 2 (0.1 ng) - MD2 analog
• ADN acarianului - TLR9 agonist
• ADN bacterian - TLR9 agonist
• Endotoxina - TLR4 agonist si MD2 analog
• Chitina - TLR2 agonist si dectin 1
26
EExtracte alergenice pt diag. xtracte alergenice pt diag.
si trat.si trat.
Alergeni recombinantiAlergeni recombinanti
• Latex : – In ultimii 20 ani, alergen foarte important.
– « Absenta Hev b5 (Hevea brasiliensiensis) in Capture Antigen poate da rezultate fals-negative la evaluarea serologica a IgE specific la latex ». (Z.Chen & al - The Journal of Allergy and Clinical Immunology, 2000).
�Hev b 5 : proteina labila.� Extracte de latex cu Hev b 5 au rezultate mai bune ?
� Sensibilitate mai buna fara a pierde din specificitate.� Mai putine rezultate fals negative.
Plus de patients + sensibilite +
27
Immuno Solid-phase AllergenChip (ISAC)
Allergen-triplet after
fluorescence-reaction
Allergen molecule
Fluorescence-labeled
secondary anti-human
IgE
IgE-antibody
(in the patient’s serum)
4 reaction sites
28
Caz ClinicCaz Clinic
• Clinician: diagnostic si decizie:– Rinita Alergica
• La acarieni cu agravare in timpul sezonului de polenizare a mesteacanului.
• Polisensibilizare la polen de iarba, frasin si mesteacan.
– Diareea ?
• Suspiciune de sensibilizare la Arahide, Soia, Creveti, Griu si Mustar.
– Probabil o “Reactie incrucisata” cu mesteacanul (alune, arahide, nuci & soia)
» Nu este necesara evictarea.
– Alergia reala este la creveti, mustar si griu :
»» Evitare !Evitare !
– Urmatorul pas
• Test Oral de provocare cu arahidele si alunele.
29
Prezicerea reactiilor incrucisatePrezicerea reactiilor incrucisate
• PR-10 protein, Bet v 1 homologue
– O proteina labila la caldura, aimentele gatite sunt frecvent tolerate.
– Frecvent asociata cu simptome locale ca syndromul oral alergic
(OAS).
– Frecvent asociat cu reactii alergice la fructe si vegetale in nordul
Europei.
Mal d 1
Dau c 1
Pru p 1
Ara h 8
Cor a 1.01 Cor a 1.04
Api g 1
Gly m 4
Bet v 1
Alergeni Alergeni –– rol terapeuticrol terapeutic
G. Passalacqua, GW Canonica. AIT (allergen immunotherapy): a model for the “precision medicine” �Clin Mol Allergy (2015) 13:24
31
Imunoterapie cu alergenImunoterapie cu alergen
32
Sindromul Oral Alergic (OAS)
• Oral Allergy Syndrome : allergic reactions that
occur rapidly, within minutes of eating a trigger
food.
– An itching or burning sensation in the lips, mouth,
and/or pharynx.
• Associated to a sensitization in one or more
proteins like PR-10 (Bet v 1-like) (birch).
1 60
Birch MGVFNYETET TSVIPAARLF KAFILDGDNL FPKVAPQAIS SVENIEGNGG PGTIKKISFP
Hazel MGVFNYETES TSVIPAARLF KAFILDGNNL IPKVAPQAVS SVENVEGNGG PGTIKKITFS
Alder MGVFNYEAET PSVIPAARLF KAFILDGDKL LPKVAPEAVS SVENIEGNGG PGTIKKITFP
Hornbeam MGVFNYEAET TSVIPAARLF KAFILDGNNL IPKVAPQAVS SVENVEGNGG PGTIKKITFS
Beech MGVFTYESEN TSVIPPARLF KAFVLDADNL IPKVAPQSIK STETLEGDGG PGTIKKITFG
Apple MGVFNYETET TSVIPAPRLF KAFILDGDNL IPKIAPQAIK STEIIEGDGG VGTIKKVTFG
Cherry MGVFTYESEF TSEIPPPRLF KAFVLDADNL VPKIAPQAIK HSEILEGDGG PGTIKKITFG
Apricot MGVFTYETEF TSVIPPEKLF KAFILDADNL IPKVAPTAVK GTEILEGDGG VGTIKKVTFG
Pear MGLYTFENEF TSEIPPPRLF KAFVLDADNL IPKIAPQAIK HAEILEGNGG PGTIKKITFG
Medicago MGVFNFEDET TSIVAPARLY KALVTDSDNL IPKVI.DAIQ SIEIVEGNGG AGTIKKLTFV
Garden pea MGVFNVEDEI TSVVAPAILY KALVTDADNL TPKVI.DAIK SIEIVEGNGG AGTIKKLTFV
Soybean MGVFTFEDEI NSPVAPATLY KALVTDADNV IPKAL.DSFK SVENVEGNGG PGTIKKITFL
Tomato MGVNTYTYES TTTISPTRLF KALVLDFDNL VPKLLSQHVK NNETIEGDGG VGSIKQMNFV
Celery MGVQKTVVEA PSTVSAEKMY QGFLLDMDTV FPKVLPQLIK SVEILEGDGG VGTVKLVHLG
Carrot MGAQSHSLEI TSSVSAEKIF SGIVLDVDTV IPKAAPGAYK SVDV.KGDGG AGTVRIITLP
Asparagus MSSSAVSHEI ESSVSAARLF KASMIEWHNL APKILPEIVS SASVVAVDGG VGSIRQINFT
120
Birch EGFPFKYVKD RVDEVDHTNF KYNYSVIEGG PIGDTLEKIS NEIKIVATPD GGSILKISNK
Hazel EGSPFKYVKE RVEEVDHTNF KYSYTVIEGG PVGDKVEKIC NEIKIVAAPD GGSILKISNK
Alder EGSPFKYVKE RVDEVDRVNF KYSFSVIEGG AVGDALEKVC NEIKIVAAPD GGSILKISNK
Hornbeam EGSPVKYVKE RVEEVDHTNF KYSYTVIEGG PVGDKVEKIC NEIKIVAAPD GGSILKITSK
Beech EGSQFKYVKH RIDEVDQANF SYGYSVIEGD VVSGIIEKIS YEIKIVASPD GGSLLKSTSK
Apple EGSQYGYVKQ RVNGIDKDNF TYSYSMIEGD TLSDKLEKIT YETKLIASPD GGSIIKTTSH
Cherry EGSQYGYVKH KIDSIDKENY SYSYTLIEGD ALGDTLEKIS YETKLVASPS GGSIIKSTSH
Apricot EGSQYAYVKH RVDGIDKDNL SYSYTLIEGD ALSDVIENIA YDIKLVASPD GGSIVKTTSH
Pear EGSQYGYVKH RVDSIDEASY SYAYTLIEGD ALTDTIEKIS YEAKLVASGS .GSTIKSISH
Medicago EGGETKYDLH KVDLVDDVNF AYNYSIVGGG GLPDTVEKIS FESKLSAGPD GGSIAKLTVK
Garden pea EDGETKHVLH KVELVDVANL AYNYSIVGGV GFPDTVEKIS FEAKLSAGPN GGSIAKLSVK
Soybean EDGETKFVLH KIESIDEANL GYSYSVVGGA ALPDTAEKIT FDSKLVAGPN GGSAGKLTVK
Tomato EGGPIKYLKH KIHVIDDKNL ETKYSLIEGD ILGEKLESIT YDIKFEANDN GGCVYKTTTE
Celery EATEYTTMKQ KVDVIDKAGL AYTYTTIGGD ILVDVLESVV NEFVVVPT.D GGCIVKNTTI
Carrot EGSPITSMTV RTDAVNKEAL TYDSTVIDGD ILLGFIESIE THLVVVPTAD GGSITKTTAI
Asparagus SAMPFPYLKE RLDFVDEANF ECKSSLIEGG DLGTKLESAS SHFKLVPSSN GGCVVKLEGI
178
Birch YHTKGDHEVK AEQVKASKEM GETLLRAVES YLLAHSDAYN ~~~~~~~~~~ ~~~~~~~~
Hazel YHTKGDHEVD AEHIKGGKEK VEGLFRAVEA YLLAHSDAYN ~~~~~~~~~~ ~~~~~~~~
Alder FHTKGDHEIN AEQIKIEKEK AVGLLKAVES YLLAHSDAYN ~~~~~~~~~~ ~~~~~~~~
Hornbeam YHTKGDHEVP AEHIKGGKER VEGLLKPVEA YLLAHTAEYN N~~~~~~~~~ ~~~~~~~~
Beech YHIKGNHEIK EEEVKAGKEK AAGLFKAVEA YLLAHPDAYN ~~~~~~~~~~ ~~~~~~~~
Apple YHAKGDVEIK EEHVKAGKEK ASGLFKLLEA YLLAHSDAYN ~~~~~~~~~~ ~~~~~~~~
Cherry YHTKGNVEIK EEHVKAGKEK ASNLFKLIET YLKGHPDAYN ~~~~~~~~~~ ~~~~~~~~
Apricot YHTKGDVEIK EEQVKAGKEK AAGLFKLVEA YLLANPDAYN ~~~~~~~~~~ ~~~~~~~~
Pear YHTKGDIEIK EEHVKAGKEK AHGLFKLIES YLKDHPDAYN ~~~~~~~~~~ ~~~~~~~~
Medicago YFTKGDAAPS EEEIKGGKAR GDGLFKALEG YVLANPD.Y~ ~~~~~~~~~~ ~~~~~~~~
Garden pea YFTKGDAAPS EEQLKTDKAK GDGLFKALEG YCLAHPD.YN ~~~~~~~~~~ ~~~~~~~~
Soybean YETKGDAEPN QDELKTGKAK ADALFKAIEA YLLAHPD.YN ~~~~~~~~~~ ~~~~~~~~
Tomato YHTKGDHVVS EEEHNVGRRE NHEYFQGCRS IPSRESFCLR LNIDEKESGL HVRNYACT
Celery YNTKGDAVLP EDKIKEATEK SALAFKAVEA YLLANLQFLA ~~~~~~~~~~ ~~~~~~~~
Carrot FHTKGDAVVP EENIKFADEQ NTALFKAIEA YLIAN~~~~~ ~~~~~~~~~~ ~~~~~~~~
Asparagus FKALPGVETT DEVAK.GKEM MTNAIKAAEA YLVANPTAYA ~~~~~~~~~~ ~~~~~~~~
o Hazelnut, 46%
o Apple, 39%
o Peach, 24%
o Cherry, 22%
o Nut, 21%
o Pear, 20%
o Almond, 19%
o Plume, 17%
o Brazil nut, 16%
o Potato, 15%
o Carrot, 13%
o Peanut, 10%
o Strawberry, 10%
o Orange, 9%
o Apricot, 7%
PR-10rBet v 1
rPru p 1rGly m 4rAra h 8rApi g 1.01rAln g 1rCor a 1nAct d 8rMal d 1rDau c 1
Ipoteza igieneiNastere (Th2)
Crese Frati mai mari Copil unicInfectii (Th1) Expunerea Putine infectiiMicrobii la alergen “Steril”Animale-pet
Th1 sau toleranta Mentine Th2Sanatos Alergie
Astm
Reviewed in Strachan D, Thorax 55:S2-S10, 2000
Ipoteza IgieneiIpoteza Igienei
MAAS MAAS –– CD14 polimorfismCD14 polimorfism
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
1 7.4 54.6 403.4 2981 22000 162755
CC
TT
CT
Endotoxin level (EU/m2)
Pre
dic
ted p
rob
abili
ty f
or
sensitis
ation
p=0.004
p=0.2
p=0.7
Manchester Allergic Asthma Study. Adnan Custovic et al, JACI, 2012
Gene Gene IdentifiIdentificate ca cate ca
Inductoare a Inductoare a AtopAtopieiiei
14 GW Linkage studies (Since 1996 up to ‘2009)
Asthma and sub-phenotypes
6 screen 6p 24-21
4 screen 11q13-21
4 screen 2q14, 21-34
3 screen 1p31-36
2 screen 4q13
2 screen 5q23-31
2 screen 7p14
2 screen 12q21-24
2 screen 13q12-14
2 screen 16q21-23
1 screen 3q21-22
1 screen 14q24
1 screen 17q12-21
1 screen 20p12
1.England: Daniels SE and Cookson OCM et al: (1996) Nature, 383: 247-250
2. The Collaborative Study on the Genetics of Asthma (CSGA in USA) : (1997) Nat. Genet. 15:389-392
3. The Epidemiologic Study of the Genetics and Environment of Asthma (EGEA in French) : (1997) Am J Respir Crit Care
Med.,156:s123-129
Improvement of genetic impact of candidate SNPs by
stratification of atopy
Gene rs number OR
LTC4S rs730012
2.62
1.88
-
-
CACNG6rs192808 2.88
BL1_ht6 2.81
ALOX5
Sp1 binding
motifs in tandem-
[G-C-G-A] 5.0
NAT2-9246G>C 1.61
[T-C-A-C-G-G] 1.62
CysLTR1
-634C>T
2.89-475A>C
-336A>G
927T>C-
9.78
899G/A 6.28
CysLTR2
601 G/A -
-1220A>C -
-819T>G 2.04
+2078C>T 2.28
+2534A>G 2.02
Gene rs number OR
ADORA1
rs16851030 3.22
rs10920568 0.52
ht [A-C-G] 0.56
ADORA2
Aht [A-T] 0.33
GPR44 -466 T>C -
PTGER2
-12813 G>A 3.21
-10814 T>A -
-6179 A>G -
-616 C>G 0.64
-166G>A 2.60
PTGER3
-1709T>A 3.02
A>C 1.31
A/G 1.36
PTGER4 -1254A>G 1.90
PTGIR +1915T>C 0.37
TBXAS1 +141931 T>A 0.27
TBXA2R
+795T>C -
+795T>C 2.57
-4684C>T 0.42
RGS7BP BL3_ht2 0.47
Genetic impact on aspirin-induced asthma by SNPs of candidate genes in arachidonate pathway
Palikhe HS, Park HS: Journal of Clinical Pharmacy and Therapeutics (2008) 33, 465–47
ORs of SNPs on Candidate genes associated with asthma and sub-phenotypes including IgE
and Eosinophils counts, (2003-2010, SCH Genome Research Center)
SH Lee, JS Park, CS Park : Allergy Asthma Immunol Res. 2011:236-244
Bochkov YA et al, PNAS 2015;112:5485-5490
--CDHR3 mediates RVCDHR3 mediates RV--C entry into host cellsC entry into host cells
--rs6967330 mutation could be a risk factor for rs6967330 mutation could be a risk factor for
RVRV--C wheezing illnesses C wheezing illnesses
Identification of candidate RVIdentification of candidate RV--C receptors by C receptors by
gene expression analysisgene expression analysis
RVRV--C15 replication in HeLa cells transfected C15 replication in HeLa cells transfected
with CDHR3 cDNAwith CDHR3 cDNA
Structure modelling of RVStructure modelling of RV--C15 binding to CDHR3 receptorC15 binding to CDHR3 receptor
PTW susceptibility gene product CDHR3 PTW susceptibility gene product CDHR3
mediates rhinovirus C binding & replicationmediates rhinovirus C binding & replication
Tratament personalizatTratament personalizat
Astmul Dificil de tratatAstmul Dificil de tratat
FarmacogenomicsFarmacogenomics
All patients with same diagnosis
1
2
Responders and patientsnot predisposed to toxicity
Non-respondersand toxic
responders
Treat with alternativedrug or dose
Treat withconventionaldrug or dose
Roche AmpliChip: FDARoche AmpliChip: FDA--ApprovedApproved
HLA si HLA si
Hipersensibilitatea la MedicamenteHipersensibilitatea la Medicamente
Corticosteroizi InhalatoriCorticosteroizi Inhalatori
• Polimorphism al TBX21
• Gena ce codeaza transcriptia factorului T-bet (T-box expressed in T cells),
• Asociata cu ameliorare semnificativa a raspunsului la metacolina la copiii cu astm
Mechanismul Molecular al Rezistentei la Mechanismul Molecular al Rezistentei la GlucocorticosteroiziGlucocorticosteroizi
Cytoplasm
Nucleus
IL -2 , IL -4,IL -13
4. Diminished Binding Affinity
Spahn & Leung, Resident &
Staff Physician 1999;45:11-22.
1. Normal Binding Affinity
2. Diminished DNA Affinity
Up-regulation of GRββββ
3. Inactive GCR Complex
Glucocorticoid
GlucocorticoidReceptor
GlucocorticoidReceptor-beta
TranscriptionFactor
Rolul CRHR1 (corticotropin-realising hormone receptor1) in Raspunsul la Corticosteroizi
Analysis was based on existing clinical trial data.
CRHR1=corticotropin-releasing hormone receptor 1.
Adapted from Tantisira KG et al. Hum Mol Genet. 2004;13:1353–1359, by permission of Oxford University Press.
A
Adult Study
CAMP
A/A A/G G/G
40
30
20
10
0
Change in F
EV
1, %
B
Change in F
EV
1, %
T/G G/G
25
20
15
10
5
0
T/T
Genotype Genotype
Polimorfism genetic Polimorfism genetic
al caii 5al caii 5--LOLO
• “tipul wild” (5 motive repetitive in regiunea
promotor: GGGCGG) – 60% din populatie
• Genomul cu 3, 4, sau 6 motive repetitive (“non-
wild type”) – au un raspuns scazut la
tratamentul cu Modificatorii de Leucotriene
Polimorfismul Leukotriene C4 Sintazei si Raspunsul la LTRAs
0
10
20
30
40
50
60
70
AA AC/CC AA AC/CC
AMP Methacholine
Patients
, %
AMP=adenosine monophosphate; LTRAs=leukotriene receptor antagonists.
Currie GP, et al. Br J Clin Pharmacol. 2003;56:422–426.
Leukotriene C4
Synthase Polymorphism:
Patients With >1 Doubling Dose Improvement
Patients With <1 Doubling Dose Improvement
Polimorfismul BetaPolimorfismul Beta--2 si Raspunsul la 2 si Raspunsul la
SalbutamolSalbutamol
Lima JJ. Clin Pharmacol Ther 1999; 65:519-25
•Doza unica de 8 mg salbutamol
•Salbutamolul creste VEMS1
mai puternic si mai rapid la Arg16 homozigoti comparativ cu purtatorii de alele cu Gly
• Polimorfismul Codon 16 este determinant pt raspunsul bronchodilator la salbutamrol
Lima JJ et al. Clin Pharmacol Ther
1999; 65: 519-25
Terapii Terapii InefIneficiicieentnte e
== pierdere de banipierdere de bani
Hypertension Drugs 10-30%
ACE Inhibitors $390 million – $1.2 billion
Heart Failure Drugs 15-25%
Beta Blockers $345 million – $575 million
Asthma Drugs Asthma Drugs 40-70%
Beta-2-agonists $560 million – $1.0 billion
"Here's my
sequence..."
The New Yorker
AllergonomicsAllergonomics
New Drugs for Asthma
• Modifications of existing drugs:– Untra-longacting inhaled β2-agonists
– Modified inhaled corticosteroids
– Glucocorticosteroid receptor agonists
– New ICS/LABA combinations
• New approaches– Anti-sense against IL-3, IL-3, GM-CSF and CCR
– Anti-sense IL-4R
– Anti-IL-9 – Anti-IL-13– Anti-C5a
– Anti-Ox 40L– CXCR2 antagonist– CRTH2 antagonists
Transcription
Nucleus
DNA(GENE)
RNA
1. Antisense(ssDNA)
RNAseH
2. siRNA(dsRNA)
RISC
Promoter
4. Decoy(dsDNA)
Transcription factor
5. Aptamer(DNA or RNA)
Translation
3. ISS/ CpG motif(ssDNA)
TLR9
Immuno-
stimulation
mRNAdegradation
PROTEIN
“Blocks”receptor
function!
Competition for TF“Blocks” transcription!
Oligonucleotide Therapeutic Approaches
RNAseH
Paolo Renzi MD.
Viitorul terapeuticViitorul terapeutic
Mesaj de luat acasaMesaj de luat acasa
�� Medicina personalizata in domeniul alergiilor Medicina personalizata in domeniul alergiilor
este la inceput, in plina dezvoltareeste la inceput, in plina dezvoltare
�� Are rol in individualizarea sensibilizariiAre rol in individualizarea sensibilizarii
�� Este importanta pentru tratament general si Este importanta pentru tratament general si
specific alergologicspecific alergologic
Discriminare Genetica