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

62

Va multumesc !

deleanudiana@yahoo.comdeleanudiana@yahoo.com

diana.deleanu@umfcluj.rodiana.deleanu@umfcluj.ro