lecture series may 2017 - federa · lecture series may 2017 ros –cgmp –drug discovery validity...
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HaraldHHWSchmidtMaastrichtUniversity,Pharmacology&PersonalisedMedicine
LECTURE SERIES MAY 2017ROS – cGMP – Drug Discovery
Validityofanimalstudiesformedicine
AnimalstudiesforMedicine
Basic Animal(Pre-clinical) Clinical Translation,
Valorisation
AnimalstudiesnotforMedicine
Basic Animal(Pre-clinical) Clinical
Translation,Valorisation
PublicationsFunding
Industry
Thetranslationalcrisisinmedicine
• Translation=DrugR&D• Reasons
• Definitionofdisease• Pre-clinicaldataquality• Publicationbias
• Waysforward• pRCTs• SR/MA,pre-clinicaltrials.org
Drugdiscovery:15+Yearstomarket
R&Dexpenditure
EROOM’sLawInefficientdrugR&Dexpenditure(NME/billionUS$)
Nosengo 2016,Nature534(7607):314–6
Innovationpertherapeuticarea
Santosetal.2017NRDD
Reasonsforterminationofdrugdevelopment
Thetargetvalidationroadblock
Theexamplestroke
Thetranslationalcrisisinmedicine
• Translation=DrugR&D• Reasons
• Definitionofdisease• Pre-clinicaldataquality• Publicationbias
• Waysforward• pRCTs• SR/MA,pre-clinicaltrials.org
NatureReviewsDrugDiscovery2010;9:834
PatrickVallance,SVPR&Dgsk
I…thinkthatstudyingrarediseasesbeginstoforeshadowhowcommondiseasesmighteventuallyfragment.Currently,manyofthediseaselabelswehavearenineteenthortwentiethcenturydefinitions...Theyarenotmolecularorcellularclassificationsofsubtypes.So,aswefragmentcommondiseases…theystarttolook…likerarediseases.Itmaybealongtimebeforewegetthere,butthatisthedirectioninwhichweseemtobegoing.
Vallance P2010NatureReviewsDrugDiscovery9:834
PatrickVallance,SVPR&Dgsk
Diseasedefinitions
• Byorgan• Heartfailure• Nephropathy
• Bydoctor• Alzheimer• Parkinson• Crohn
• Bysymptom• Hypertension• Pulmonaryhypertension• Peripheralarterydisease• Stroke• Inflammatorybowldisease• Rheumatoidarthritis• Psoriasis• Depression
Rarediseases(A…)
• Bymechanism• Aceruloplasminemia• AcetylCoAacetyltransferase2deficiency• Acetyl-carnitinedeficiency• ACTHdeficiency• ACTHresistance• Acyl-CoAoxidasedeficiency• Adeninephosphoribosyltransferase deficiency• Adenosinemonophosphatedeaminase1deficiency• Adenosylhomocysteine hydrolasedeficiency• Adenylosuccinase deficiency…
3-methylglutaconicaciduria
Aarskog-Scottsyndrome
ABCDsyndrome
Abetalipoproteinemia
26
Achondrogenesis_Ib
Achondroplasia
Achromatopsia
Acquiredlong_QT_syndrome
Acromegaly
Adenocarcinoma
Adenoma,periampullary
Adenomas
Adenosine_deaminasedeficiency
Adrenocorticalcarcinoma
Adult_iphenotype
Afibrinogenemia
Alagillesyndrome
Albinism
Alcoholdependence
Alexanderdisease
Allergicrhinitis
96
Alzheimerdisease
Amyloidneuropathy
Amyloidosis
Amyotrophiclateral
sclerosis
Androgeninsensitivity
Anemia
Angelmansyndrome
Angiofibroma,sporadic
117
Aniridia,type_II
Anorexianervosa
126
129
Aorticaneurysm
Apertsyndrome
Apolipoproteindeficiency
137
Aquaporin-1deficiency
144
Arthropathy
Aspergersyndrome
Asthma
Ataxia
Ataxia-telangiectasia
Atelosteogenesis
Atherosclerosis
Atopy
Atrialfibrillation
Atrioventricularblock
Autism
Autoimmunedisease
Axenfeldanomaly
182
Bare_lymphocytesyndrome
Barthsyndrome
Bart-Pumphreysyndrome
Basal_cellcarcinoma
192
Beckermusculardystrophy
Benzenetoxicity
198
Birt-Hogg-Dubesyndrome
Bladdercancer
Bloodgroup
217
Bothniaretinal
dystrophy
Branchiooticsyndrome
Breastcancer
Brugadasyndrome
Butterflydystrophy,
retinal
Complement_componentdeficiency
Cafe-au-laitspots
Caffeydisease
Cancersusceptibility
Capillarymalformations
Carcinoidtumors,
intestinal
Cardiomyopathy
Carneycomplex
275
Cataract
287
Cerebellarataxia
Cerebralamyloid
angiopathy
Cervicalcarcinoma
Charcot-Marie-Toothdisease
Cleftpalate
Coatsdisease
Coffin-Lowrysyndrome
Coloboma,ocular
Coloncancer
347
Conedystrophy
Convulsions
Cornealdystrophy
Coronaryartery
disease
Costellosyndrome
Coumarinresistance
Cowdendisease
CPTdeficiency,
hepatic
Cramps,potassium-aggravated
377
378
379
Craniosynostosis
Creatinephosphokinase
Creutzfeldt-Jakobdisease
Crouzonsyndrome
Cutislaxa
396
Deafness
Dejerine-Sottasdisease
Dementia
Dentindysplasia,
type_II418
Denys-Drashsyndrome
422
Desmoiddisease
Diabetesmellitus
Diastrophicdysplasia
434
439
441
Duchennemusculardystrophy
Dyserythropoieticanemia
Dysfibrinogenemia463
EBD
Ectodermaldysplasia
Ectopia
Ehlers-Danlossyndrome
Elliptocytosis
474
Emphysema
Endometrialcarcinoma
EnhancedS-cone
syndrome
Enlargedvestibularaqueduct
Epidermolysisbullosa
Epidermolytichyperkeratosis
Epilepsy
Epiphysealdysplasia
Episodicataxia
Epsteinsyndrome
Erythrokeratoderma
Esophagealcancer
Estrogenresistance
Exudativevitreoretinopathy
Eyeanomalies
Factor_xdeficiency
Fanconianemia
Fanconi-Bickelsyndrome
Favism
Fechtnersyndrome
Fovealhypoplasia
549
Frasiersyndrome
558
Fundusalbipunctatus
G6PDdeficiency
Gardnersyndrome
Gastriccancer
Gastrointestinalstromaltumor
Germ_celltumor
Gerstmann-Strausslerdisease
Giant-cellfibroblastoma
Glaucoma
Glioblastoma
594
604
Goiter
GRACILEsyndrome
Graft-versus-hostdisease
Gravesdisease
Growthhormone
HDL_cholesterollevel_QTL
Heartblock
Hemangioblastoma,cerebellar
Hematopoiesis,cyclic
Hemiplegic_migraine,familial
Hemolyticanemia
Hemolytic-uremicsyndrome
Hemorrhagicdiathesis
665
Hepaticadenoma
Hirschsprungdisease
Histiocytoma
HIV
Holoprosencephaly
Homocystinuria
Huntingtondisease
Hypercholanemia
Hypercholesterolemia
Hypereosinophilicsyndrome
Hyperinsulinism
733
Hyperlipoproteinemia
Hyperostosis,endosteal
Hyperparathyroidism
Hyperproinsulinemia
Hyperprolinemia
Hyperproreninemia
Hypertension
Hyperthroidism
Hyperthyroidism
Hypertriglyceridemia
Hypoalphalipoproteinemia
Hypobetalipoproteinemia
Hypocalcemia
Hypocalciurichypercalcemia
Hypoceruloplasminemia
Hypochondroplasia
Hypodontia
Hypofibrinogenemia
Hypoglycemia
Hypokalemicperiodicparalysis
Hypothyroidism
792
Ichthyosiformerythroderma Ichthyosis
IgE_levelsQTL
803
Incontinentiapigmenti
Infantile_spasmsyndrome
809
Insensitivityto_pain
Insomnia
Insulinresistance
Intervertebral_discdisease
Iridogoniodysgenesis
Iris_hypoplasiaand_glaucoma
Jackson-Weisssyndrome
Jensensyndrome
830
833
Kallmannsyndrome
Keratitis
843
Keratoconus
845
847
Kniestdysplasia
Larsonsyndrome
868
Leanness,inherited
Lebercongenital_amaurosis
Leighsyndrome
Leopardsyndrome
Leprechaunism
Leprosy
Leukemia
Lhermitte-Duclossyndrome
Liddlesyndrome
LiFraumenisyndrome
Li-Fraumenisyndrome
Lipodystrophy
Lipoma
Lissencephaly
Listeriamonocytogenes
Loeys-Dietzsyndrome
Long_QTsyndrome
913
Lungcancer
Lymphoma
930
Macrocyticanemia
Macrothrombocytopenia
Maculardegeneration
Maculopathy,bull’s-eye
Malaria
942
Maple_syrup_urinedisease
Marfansyndrome
Marshallsyndrome
MASSsyndrome
Mast_cellleukemia
959
May-Hegglinanomaly
McCune-Albrightsyndrome
Medulloblastoma
Melanoma Memoryimpairment
Menieredisease
Meningioma
Menkesdisease
Mentalretardation
Merkel_cellcarcinoma
Mesangialsclerosis
Mesothelioma
Migraine
1016
Miyoshimyopathy
MODY
Mohr-Tranebjaergsyndrome
Morningglorydisc
anomaly
Muenkesyndrome
Muir-Torresyndrome
Multipleendocrineneoplasia
Musculardystrophy
Myasthenicsyndrome
Myelodysplasticsyndrome
Myelofibrosis,idiopathic
Myelogenousleukemia
Myeloperoxidasedeficiency
Myocardialinfarction
Myoclonicepilepsy
1056
1057
Myopathy
Myotilinopathy
Myotoniacongenita
Myxoma,intracardiac
Nasopharyngealcarcinoma
Nephropathy-hypertension
Nethertonsyndrome
Neuroblastoma
Neuroectodermaltumors
Neurofibromatosis
1096
Neurofibromatosis
Neurofibrosarcoma
Neuropathy
Neutropenia
Nevosyndrome
11041105
Nicotineaddiction
Nightblindness
Nijmegen_breakagesyndrome
1113
Non-Hodgkinlymphoma
Nonsmall_celllung_cancer
Noonansyndrome
Norriedisease
Obesity
Obsessive-compulsivedisorder
Occipital_hornsyndrome
Oculodentodigitaldysplasia
Oligodendroglioma
Oligodontia
1140
Omennsyndrome
Opticatrophy
Orolaryngealcancer
OSMEDsyndrome
Osseousheteroplasia
1153
Osteoarthritis
Osteogenesisimperfecta
Osteopetrosis
Osteoporosis 1164
Osteosarcoma
Ovariancancer
1174
Pancreaticcancer
1183
Paragangliomas
Paramyotoniacongenita
Parathyroidadenoma
Parietalforamina
Parkes_Webersyndrome
Parkinsondisease
Partingtonsyndrome
PCWH
Pelizaeus-Merzbacherdisease
Pendredsyndrome
Perinealhypospadias
Petersanomaly
Peutz-Jegherssyndrome
Pfeiffersyndrome
Pheochromocytoma
Pickdisease
Piebaldism
1229
Pilomatricoma
1232
Placentalabruption
Plateletdefect/deficiency
1239
Polycythemia
Polyposis
PPM-Xsyndrome
Preeclampsia
Primarylateral_sclerosis
1263
1267
Prostatecancer
Proudsyndrome
Pseudoachondroplasia
Pseudohypoaldosteronism
Pseudohypoparathyroidism
Pyropoikilocytosis
1297
Rabson-Mendenhallsyndrome
Renal_cellcarcinoma
Retinal_conedsytrophy
Retinitispigmentosa
Retinoblastoma
Rettsyndrome
Rhabdomyosarcoma
Rheumatoidarthritis
Rh-modsyndrome
Rh-negativeblood_type
Riegersyndrome
Ring_dermoidof_cornea
Rippling_muscledisease
Roussy-Levysyndrome
Rubenstein-Taybisyndrome
Saethre-Chotzensyndrome
Salivaryadenoma
1347
SARS,progression_of
Schizophrenia
Schwannomatosis
Sea-blue_histiocytedisease
Seasonalaffective_disorder
Sebastiansyndrome
Self-healingcollodion_baby
Sepsis
1383
Sezarysyndrome
Shah-Waardenburgsyndrome
Shprintzen-Goldbergsyndrome
Sick_sinussyndrome
1396
Simpson-Golabi-Behmelsyndrome
1401
SMEDStrudwick_type
1414
Somatotrophinoma
Spastic_ataxia/paraplegia
Spherocytosis
Spinal_muscularatrophy
Spinocereballarataxia
1432
Spondyloepiphysealdysplasia
Squamous_cellcarcinoma
Stargardtdisease
Sticklersyndrome
Stomachcancer
Stroke
1456
Supranuclearpalsy
Supravalvar_aorticstenosis
Syndactyly
Systemic_lupuserythematosus
Tangierdisease
1476
T-celllymphoblastic
leukemia
Tetralogyof_Fallot
1490
Thrombocythemia
Thrombocytopenia
Thrombophilia
Thyroidcarcinoma
Thyrotoxicperiodicparalysis
Tietzsyndrome
Toenaildystrophy,
isolated
1518
1528
Turcotsyndrome
1545
Urolithiasise
Ushersyndrome
Uterineleiomyoma
van_Buchemdisease
1555
Ventriculartachycardia
Verticaltalus
Viralinfection
Vitelliformmacular
dystrophy
Vohwinkelsyndrome
von_Hippel-Lindausyndrome
Waardenburg-Shahsyndrome
Waardenburgsyndrome
Wagnersyndrome
WAGRsyndrome
Walker-Warburgsyndrome
Watsonsyndrome
Wegenergranulomatosis
Weill-Marchesanisyndrome
1586
Williams-Beurensyndrome
Wilmstumor
Wiskott-Aldrichsyndrome
Witkopsyndrome
Wolff-Parkinson-Whitesyndrome
1614
Zlotogora-Ogursyndrome
Adrenaladenoma
Adrenal_corticalcarcinoma
Aneurysm,familial_arterial
Autoimmunethyroiddisease
Basal_cellnevus_syndrome
Carcinoid_tumorof_lung
Central_coredisease
Coronaryspasms
2385
2785
Maculardystrophy
Medullary_thyroidcarcinoma
Pancreaticagenesis
3212
3229
Thyroidhormoneresistance
3512
3558
Combinedimmunodeficiency
Multiplemalignancysyndrome
Optic_nervehypoplasia/aplasia
5233
Renaltubularacidosis
Multiplesclerosis
Renaltubular
dysgenesis
ABCA1
ABCA4
ADA
ADRB2
AGRP
JAG1
AGTAGTR1
ALOX5
ALOX5AP
APC
APOA1
APOA2
APOB
APOE
APPFAS
AQP1
AR
STS
ATM
ATP1A2
ATP7A
BAX
CCND1
BCS1L
BDNF
BMPR1A
BRCA1
BRAF
BRCA2
C6
CACNA1A
CACNA1S
CACNB4
CASP8
CASP10
CASR
CAV3
RUNX1
CBS
CD36
CDH1
CDKN2A
CHRNA4
COL1A1
COL1A2
COL2A1
COL3A1
COL7A1
COL8A2
COL9A2
COL9A3
COL11A1
COL11A2
COMP
KLF6
COX15
CP
CPT2
CRX
CRYAB
NKX2-5
CTLA4
CTNNB1
CYP1B1
CYP2A6
DBH
ACE
DCTN1
DCX
DES
TIMM8A
COCH
NQO1
DMDDSP
DSPP
SLC26A2
ECE1
EDN3
EDNRB
EGFR
EGR2
ELA2
ELN
EP300
EPHX1ERBB2
EYA4
ESR1
EYA1
F5
F7
FBN1
FCGR3A
FCMD
FGA
FGB
FGD1
FGFR1
FGFR3
FGFR2
FGG
FOXC1
FLNB
G6PD
GABRG2
GARS
GATA1
GCK
GCNT2
GCSL
GDNF
GJA1
GJB2GJB3
GPC3
GNAI2GNAS
GSS
MSH6
GYPC
GUCY2D
HEXB
CFH
HNF4A
HOXD10
HRAS
HSD11B2
HSPB1
HTR2A
IL2RG
IL10
IL13
INS
INSR
IPF1
IRF1
JAK2
KCNE1
KCNH2
KCNJ11
KCNQ1
KCNQ2
KIT
KRAS
KRT1
KRT10
LAMA3
LMNA
LOR
LPP
LRP5
SMAD4
MAPT
MATN3
MECP2
MEN1
MET
CIITA
MITF
MLH1 NR3C2
MPO
MPZ
MSH2
MSX1
MSX2
MUTYH
MXI1
MYF6MYH6
MYH7
MYH8
MYH9
MYO7A
NBN
NDP
NDUFV1
NDUFS4
NF1
NF2
NOS3
NRL
NTRK1
OPA1
SLC22A18
PAFAH1B1
PARK2
PAX3
PAX6
PAX9
PDGFB
PDGFRA
PDGFRL
PDE6B
PDHA1
ENPP1
SLC26A4
PGK1
SERPINA1
PIK3CA
PITX2 PITX3
PLEC1
PLOD1
PLP1
PMP22
PMS2
PPARG
PRKAR1A
PRNP
PRODH
PSEN1
PTCH
PTEN
PTPN11
PTPRC
PVRL1
RAG1
RAG2
RASA1
RB1
RDS
REN
RET
RHAG
RHCE
RHO
RLBP1
RP1
RPGR
RPE65
RPS6KA3
RYR1
RYR2
SCN4A
SCN5A
SCNN1B
SCNN1G
SDHA
SDHBSDHD
SGCD
SHH
SLC2A2
SLC4A1
SLC6A4
SLC6A8
SLC34A1
SNCA
SOX3
SOX10
SPTA1
SPTB
STAT5B
ELOVL4
STK11
ABCC8
TAP2
TAZ
TBP
TCF1
TCF2
TG
TGFBR2
TGM1
THBD
TNF
TP53
TPO
TSHR
TTN
TTR
TYR
USH2A
VHL
VMD2
WAS
WT1
XRCC3
PLA2G7
HMGA2
DYSF
AXIN2
MAD1L1
RAD54L
IKBKG
TCAP
PTCH2
WISP3
BCL10
PHOX2B
LGI1
VAPB
MYOT
KCNE2
NR2E3
USH1C
FBLN5
POMT1
GJB6
SPINK5
CHEK2
ACSL6
CRB1
AIPL1
RAD54B
PTPN22
BSCL2
VSX1FOXP3
PHF11
PRKAG2
NLGN3
CNGB3
RETN
RPGRIP1
NLGN4X
ALS2
CDH23
DCLRE1C
PCDH15
CDC73
OPA3
BRIP1
MASS1
ARX
FLCN
Abacavirhypersensitivity
18
Acrocallosalsyndrome
Acrocapitofemoraldysplasia
Acrokeratosisverruciformis
Acromesomelicdysplasia
53
Adrenoleukodystrophy
Adrenomyeloneuropathy
ADULTsyndrome
Agammaglobulinemia
AIDS
77
AldosteronismAlopecia
universalis
Alperssyndrome
87
Alpha-actinin-3deficiency
92
Alportsyndrome
Amelogenesisimperfecta
Analbuminemia
107
Andersondisease
Anhaptoglobinemia
Ankylosingspoldylitis
Antley-Bixlersyndrome
Aplasticanemia
Aromatasedeficiency
Arthrogryposis
162
Atransferrinemia
Atrichia w/papular lesions
171
Bardet-Biedlsyndrome
BCGinfection
Beckwith-Wiedemannsyndrome
Bernard-Souliersyndrome
Bethlemmyopathy
Blausyndrome
210
Blepharospasm
Blue-conemonochromacy
Bombayphenotype
Bosley-Salih-Alorainysyndrome
Brachydactyly
Buschke-Ollendorffsyndrome
Calcinosis,tumoral
Campomelicdysplasia
Cartilage-hairhypoplasia
279
292
294Ceroid
lipofuscinosis
Ceroid-lipofuscinosis
CETPdeficiency
Cholelithiasis
Cholestasis
313
Chondrocalcinosis
Chondrosarcoma
Chorea,hereditary
benign
320
Chudley-Lowrysyndrome
329
Chylomicronretentiondisease
Ciliarydyskinesia
CINCAsyndrome
Cleidocranialdysplasia
Cockaynesyndrome
Codeinesensitivity
344
Colorblindness
Congestiveheartfailure
Conjunctivitis,ligneous
357
Coproporphyria
Craniometaphysealdysplasia
CRASHsyndrome
Crigler-Najjarsyndrome
Crohndisease
Cystathioninuria
Cysticfibrosis
CystinuriaDarierdisease
Debrisoquinesensitivity
Dentalanomalies,
isolated
Dentdisease
De Sanctis-Cacchionesyndrome
DiGeorgesyndrome
438
Dosage-sensitivesex
reversal
Double-outletright ventricle
Downsyndrome
452
453
Dyskeratosis
Dysprothrombinemia
461
Dystonia
EEC syndrome
471
Ellis-van Creveldsyndrome
Enchondromatosis
Erythremias
Erythrocytosis
Ewingsarcoma
Exostoses
527
Fertileeunuch
syndrome
535
Fibromatosisl
539
Fish-eyedisease
Fitzgerald factordeficiency
544
545
Frontometaphysealdysplasia
Fumarasedeficiency
Gaucherdisease
584
Gilbertsyndrome
GM-gangliosidosis
Greenbergdysplasia
626
Guttmachersyndrome
Haim-Munksyndrome
Hand-foot-uterussyndrome
Harderoporphyrinuria
HARPsyndrome
Hay-Wellssyndrome
646
Heinzbody
anemia
HELLPsyndrome
Hemangioma
Hematuria,familial_benign
Hemochromatosis
Hemoglobi_Hdisease
Hemophilia
Heterotaxy
Heterotopia
Hex_Apseudodeficiency
679
Homocysteineplasma
level
699 701
Hoyeraal-Hreidarssonsyndrome
HPFH
HPRT-relatedgout
H._pyloriinfection
Hyalinosis,infantilesystemic
Hydrocephalus
Hyperalphalipoproteinemia
Hyperandrogenism
Hyperbilirubinemia
Hyperekplexia
727
Hyper-IgDsyndrome
734
Hypermethioninemia
Hyperphenylalaninemia
Hyperprothrombinemia
Hypertrypsinemia
Hyperuricemicnephropathy
Hypoaldosteronism
Hypochromicmicrocytic
anemia
Hypogonadotropichypogonadism
Hypohaptoglobinemia
Hypolactasia,adulttype
780
Hypophosphatasia
Hypophosphatemia
Hypophosphatemicrickets
785
Hypoprothrombinemia
Inclusionbody
myopathy
Ironoverload/deficiency
Joubertsyndrome
Juberg-Marsidisyndrome
Kanzakidisease
Kartagenersyndrome
Kenny-Caffeysyndrome-1
Kininogendeficiency
Langermesomelicdysplasia
Larondwarfism
LCHADdeficiency
Leadpoisoning
Leiomyomatosis
Leri-Weilldyschondrosteosis
Lesch-Nyhansyndrome,
891
Leydigcell
adenoma
LIG4syndrome
Limb-mammarysyndrome
Lipoproteinlipase
deficiency
Longevity
Lowesyndrome
Low reninhypertension
Lymphangioleiomyomatosis
Lymphedema
945
MASAsyndrome
McKusick-Kaufmansyndrome
969
Melnick-Needlessyndrome
982
Meningococcaldisease
Mephenytoinpoor metabolizer
Metachromaticleukodystrophy
Metaphysealchondrodysplasia
Methemoglobinemia
10011002
Mevalonicaciduria
Microcephaly
Micropenis
Microphthalmia
Muckle-Wellssyndrome
Mucopolysaccharidosis
Mycobacterialinfection
Myelokathexis,isolated
1050
Myeloproliferativedisorder
Nemalinemyopathy
1080
Nephrolithiasis
Nephronophthisis
1090
Neurodegeneration
Nonakamyopathy
Norumdisease
1119
Ocularalbinism
1133
Odontohypophosphatasia
Opremazolepoor metabolizer
Orofacial cleft
Osteolysis
Osteopoikilosis
Otopalatodigitalsyndrome
Ovarioleukodystrophy
Pachyonychiacongenita
Pagetdisease
Pallister-Hallsyndrome
Palmoplantarkeratoderma
Pancreatitis
Papillon-Lefevresyndrome
Pelger-Huetanomaly
Periodontitis
Phenylketonuria
1227 Plasminogendeficiency
1238
Polydactyly
Poplitealpterygiumsyndrome
Porphyria
Precociouspuberty,
male
Prematureovarianfailure
1265
Proguanilpoor metabolizer
Proteinuria
Pseudohermaphroditism,male
Psoraisis
Pulmonaryfibrosis
RAPADILINOsyndrome
Rapp-Hodgkinsyndrome
Red hair/fair skin
Refsumdisease
Restingheartrate
Restrictivedermopathy,
lethal
1325
1335
Rothmund-Thomsonsyndrome
Salladisease
Sarcoidosis
Schindlerdisease
1361
Senior-Lokensyndrome
1376
Septoopticdysplasia
Sexreversal
Shortstature
Sialidosis
Sialuria
Sicklecell
anemia
Situsambiguus
Smith-Fineman-Myerssyndrome
Smith-McCortdysplasia
Sotossyndrome
Spinabifida
Split-hand/footmalformation
Spondylometaphysealdysplasia
1438
Startledisease
STAT1deficiency
Steatocystomamultiplex
1446
Surfactantdeficiency
Sutherland-Haansyndrome-like
1466
Symphalangism,proximal
Synostosessyndrome
Synpolydactyly
Tallstature
1475
Tay-Sachsdisease
Thalassemias
Thymine-uraciluria
Tolbutamidepoor
metabolizer
1519
Trichodontoosseoussyndrome
Trichothiodystrophy
1526
Tropicalcalcific
pancreatitis
Tuberculosis
Tuberoussclerosis
Twinning,dizygotic
1542
UV-inducedskin damage
Velocardiofacialsyndrome
Virilization
1565
1580
Weaversyndrome
Weyersacrodentaldysostosis
WHIMsyndrome
Wolframsyndrome
Wolmandisease
Xerodermapigmentosum
1611
Yellownail
syndrome
Zellwegersyndrome
Adrenocorticalinsufficiency
Chondrodysplasia,Grebetype
2327
Combinedhyperlipemia
2354
Diabetesinsipidus
3037
3144
Ovariandysgenesis
3260van_der_Woude
syndromeBasal
gangliadisease
42915170
Pituitaryhormonedeficiency
Renalhypoplasia,
isolated
Ovariansex cordtumors
CombinedSAP deficiency
Multiplemyeloma
SERPINA3
ACTN3
ADRB1
NR0B1
ALAD
ALB
ABCD1
ALPL
ATP2A2
ATRX
AVPR2
FOXL2
BTK
RUNX2KRIT1
CETP
CTSC
CFTR
CLCN5COL4A4
COL6A1
COL6A2
COL6A3
COL10A1
CPOX
CTH
CYP2C19
CYP2C9
CYP2D6
CYP11B1
CYP11B2
CYP19A1
CYP21A2
DKC1
DLX3
DNAH5
DPYD
DRD5
ERCC2
ERCC3
ERCC5
ERCC6
EVC
EWSR1
EXT1
F2
F9
FH
FOXC2
FLNA
FLT4
FSHR
FTL
NR5A1
FUT2OPN1MW
GHR
GLB1
GLI3
GLRA1
GNRHR
GP1BB
HADHA
HBA1
HBA2
HBB
HEXA
HFE
HLA-B
HOXA1
HOXA13HOXD13
HP
HPRT1
HSPG2
IFNG
IFNGR1
IHHIRF6
KNG1
KRT16
KRT17
L1CAM
LBR
LCAT
LHCGR
LIG4
LIPA
LPL
MAT1A
MBL2
MC1R
MCM6
MTHFD1
MTR MTRR MVK
NAGA
NPHP1
ROR2
OCRL
PAH
PAX2
PDGFRB
PEX1
PEX7
PEX10
PEX13
ABCB4
PLG
POLG
POR
PPT1
PSAPPTHR1
PXMP3
PEX5
OPN1LW
RMRP
SFTPC
SHOX
SLC3A1
SOX9
SPINK1
STAT1
TBX1
TBCE
TERC
TF
TITF1
TPM2
TSC1TSC2
UMOD
WFS1
CXCR4
FGF23
MKKS
GDF5
TP73L
DNAH11
TNFRSF11A
HESX1
EIF2B4
EIF2B2EIF2B5
NOG
RECQL4
GNEENAM
ZMPSTE24
LEMD3
SLC17A5
DNAI1
SAR1B
SLC45A2
UGT1A1
DYM
BCOR
PEX26
HR
CFC1
ANKH
CARD15
NSD1
VKORC1
MCPH1
PANK2
CIAS1
ANTXR2
NPHP4
The human disease networkGoh K-I, Cusick ME, Valle D, Childs B, Vidal M, Barabasi A-L (2007) Proc Natl Acad Sci USA 104:8685-8690′
Supporting Information Figure 13 | Bipartite-graph representation of the diseasome. A disorder (circle) and a gene (rectangle) are connected if the gene is implicated in the disorder. The size of the circle represents the number of distinct genes associated with the disorder. Isolated disorders (disorders having no links to other disorders) are not shown. Also, only genes connecting disorders are shown.
Disorder Class
Disorder Name
BoneCancerCardiovascularConnective tissue disorderDermatologicalDevelopmentalEar, Nose, ThroatEndocrineGastrointestinalHematologicalImmunologicalMetabolicMuscularNeurologicalNutritionalOphthamologicalPsychiatricRenalRespiratorySkeletalmultipleUnclassified
5233 Placental steroid sulfatase deficiency5170 Ovarian hyperstimulation syndrome4291 Cerebral cavernous malformations3558 Ventricular fibrillation, idiopathic3512 Total iodide organification defect3260 Premature chromosome condensation w/ microcephaly, mental retardation3229 Pigmented adrenocortical disease, primary isolated3212 Persistent hyperinsulinemic hypoglycemia of infancy3144 Optic nerve coloboma with renal disease3037 Multiple cutaneous and uterine leiomyomata2785 Hypoplastic left heart syndrome2385 Creatine deficiency syndrome, X-linked2354 Congenital bilateral absence of vas deferens2327 Chronic infections, due to opsonin defect1614 Yemenite deaf-blind hypopigmentation syndrome1611 XLA and isolated growth hormone deficiency1586 Weissenbacher-Zweymuller syndrome1580 Warfarin resistance/sensitivity1565 Vitamin K-dependent coagulation defect1555 VATER association with hydrocephalus1545 Unna-Thost disease, nonepidermolytic1542 Ullrich congenital muscular dystrophy1528 Trismus-pseudocomptodactyly syndrome1526 Trifunctional protein deficiency1519 Transposition of great arteries, dextro-looped1518 Transient bullous of the newborn1490 Thanatophoric dysplasia, types I and II1476 Tauopathy and respiratory failure1475 Tarsal-carpal coalition syndrome1466 Sweat chloride elevation without CF1456 Subcortical laminar heterotopia1446 Stevens-Johnson syndrome, carbamazepine-induced1438 Stapes ankylosis syndrome without symphalangism1432 Spondylocarpotarsal synostosis syndrome1414 Solitary median maxillary central incisor1401 Skin fragility-woolly hair syndrome1396 Silver spastic paraplegia syndrome1383 Severe combined immunodeficiency1376 Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis1361 Schwartz-Jampel syndrome, type 11347 Sandhoff disease, infantile, juvenile, and adult forms1335 Robinow syndrome, autosomal recessive1325 Rhizomelic chondrodysplasia punctata1297 Pyruvate dehydrogenase deficiency1267 Prolactinoma, hyperparathyroidism, carcinoid syndrome1265 Progressive external ophthalmoplegia with mitochondrial DNA deletions1263 Prion disease with protracted course1239 Pneumothorax, primary spontaneous1238 Pneumonitis, desquamative interstitial1232 Pituitary ACTH-secreting adenoma1229 Pigmented paravenous chorioretinal atrophy1227 Pigmentation of hair, skin, and eyes, variation in1183 Papillary serous carcinoma of the peritoneum1174 Pallidopontonigral degeneration1164 Osteoporosis-pseudoglioma syndrome1153 Ossification of the posterior longitudinal spinal ligaments1140 Oligodontia-colorectal cancer syndrome1133 Oculofaciocardiodental syndrome1119 Norwalk virus infection, resistance to1113 Noncompaction of left ventricular myocardium1105 Newfoundland rod-cone dystrophy1104 Nevus, epidermal, epidermolytic hyperkeratotic type1096 Neurofibromatosis-Noonan syndrome1090 Neural tube defects, maternal risk of1080 Nephrogenic syndrome of inappropriate antidiuresis1057 Myokymia with neonatal epilepsy1056 Myoglobinuria/hemolysis due to PGK deficiency1050 Myelomonocytic leukemia, chronic1016 Mitochondrial complex deficiency1002 Methylcobalamin deficiency, cblG type1001 Methionine adenosyltransferase deficiency, autosomal recessive982 Melorheostosis with osteopoikilosis969 Medullary cystic kidney disease959 Mastocytosis with associated hematologic disorder945 Mandibuloacral dysplasia with type B lipodystrophy942 Malignant hyperthermia susceptibility930 Lynch cancer family syndrome II913 Lower motor neuron disease, progressive, without sensory symptoms891 Leukoencephalopathy with vanishing white matter868 Laryngoonychocutaneous syndrome847 Keratosis palmoplantaria striata845 Keratoderma, palmoplantar, with deafness843 Keratitis-ichthyosis-deafness syndrome833 Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome830 Jervell and Lange-Nielsen syndrome809 Infundibular hypoplasia and hypopituitarism803 Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked792 Hystrix-like ichthyosis with deafness785 Hypoplastic enamel pitting, localized780 Hypoparathyroidism-retardation-dysmorphism syndrome734 Hyperkeratotic cutaneous capillary-venous malformations733 Hyperkalemic periodic paralysis727 Hyperferritinemia-cataract syndrome701 Homozygous 2p16 deletion syndrome699 Homocystinuria-megaloblastic anemia, cbl E type679 High-molecular-weight kininogen deficiency665 Hemosiderosis, systemic, due to aceruloplasminemia646 Hearing loss, low-frequency sensorineural626 Greig cephalopolysyndactyly syndrome604 Glutathione synthetase deficiency594 Glomerulocystic kidney disease, hypoplastic584 Giant platelet disorder, isolated558 Fuchs endothelial corneal dystrophy549 Foveomacular dystrophy, adult-onset, with choroidal neovascularization545 Focal cortical dysplasia, Taylor balloon cell type544 Fluorouracil toxicity, sensitivity to539 Fibular hypoplasia and complex brachydactyly535 Fibrocalculous pancreatic diabetes527 Fatty liver, acute, of pregnancy474 Emery-Dreifuss muscular dystrophy471 Elite sprint athletic performance463 Dystransthyretinemic hyperthyroxinemia461 Dyssegmental dysplasia, Silverman-Handmaker type453 Dysalbuminemic hyperthyroxinemia452 Dyggve-Melchior-Clausen disease441 Dopamine beta-hydroxylase deficiency439 Dissection of cervical arteries438 Disordered steroidogenesis, isolated434 Dilated cardiomyopathy with woolly hair and keratoderma422 Dermatofibrosarcoma protuberans418 Dentinogenesis imperfecta, Shields type396 Cyclic ichthyosis with epidermolytic hyperkeratosis379 Craniofacial-skeletal-dermatologic dysplasia378 Craniofacial-deafness-hand syndrome377 Craniofacial anomalies, empty sella turcica, corneal endothelial changes357 Conotruncal anomaly face syndrome347 Colonic aganglionosis, total, with small bowel involvement344 Cold-induced autoinflammatory syndrome329 Chylomicronemia syndrome, familial320 Choreoathetosis, hypothyroidism, and respiratory distress313 Cholesteryl ester storage disease294 Cerebrovascular disease, occlusive292 Cerebrooculofacioskeletal syndrome287 Central hypoventilation syndrome279 Cavernous malformations of CNS and retina275 Carpal tunnel syndrome, familial217 Bone mineral density variability210 Blepharophimosis, epicanthus inversus, and ptosis198 Beta-2-adrenoreceptor agonist, reduced response to192 Beare-Stevenson cutis gyrata syndrome182 Bannayan-Riley-Ruvalcaba syndrome171 Attention-deficit hyperactivity disorder162 Athabaskan brainstem dysgenesis syndrome144 Arrhythmogenic right ventricular dysplasia137 Apparent mineralocorticoid excess, hypertension due to129 Anxiety-related personality traits126 Anterior segment anomalies and cataract117 Angiotensin I-converting enzyme107 Analgesia from kappa-opioid receptor agonist, female-specific96 Alternating hemiplegia of childhood92 Alpha-thalassemia/mental retardation syndrome87 Alpha-1-antichymotrypsin deficiency77 Aldosterone to renin ratio raised53 Adrenal hyperplasia, congenital26 Achondrogenesis-hypochondrogenesis, type II18 Acampomelic campolelic dysplasia
Thehumannetworkofdiseases(diseasome)
Gohetal.2006,PNAS
ThecommROCGcommon mechanism cluster
commROCG
GenebasedDiseasome
DiseasephenotypesofthecommROCGcluster
Commonmechanism-baseddrugrepurposingshortensdrugdevelopment
Nosengo 2016,Nature534(7607):314–6
Thetranslationalcrisisinmedicine
• Translation=DrugR&D• Reasons
• Definitionofdisease• Pre-clinicaldataquality• Publicationbias
• Waysforward• pRCTs• SR/MA,pre-clinicaltrials.org
≥65%ofpublishedworkisnotreproducible
Prinz etal.NatureRevDrugDisc10:712-3
Theprevalenceofirreproducibility
57.5%
Thetranslationalcrisisinmedicine
• Translation=DrugR&D• Reasons
• Definitionofdisease• Pre-clinicaldataquality• Publicationbias
• Waysforward• pRCTs• pre-clinicaltrials.org
Targetvalidationinstroke
ROS
Neurotoxicity
NOX4NOX2
Kleinschnitz et al. (2010) PLoS Biology
NOXinstroke
pRCT:Nox2 KOwithouteffectinstroke
NOX2instroke
Kleikers etal.2015Sci.Reports
Targetvalidationinstroke:NOX4iandNOS1icombinationtherapy
NOX4
ROS
NOS1
NO
sGC
ONOO-
Neurotoxicity
L-NAME
PSD-95
PSD-95i
NOS1,butnotPSD-95,isatargetinstroke
PSD-95inhibitors and stroke
Kleinschnitzetal.2016J.Cereb.BloodFlowMetab.
Thetranslationalcrisisinmedicine
• Translation=DrugR&D• Reasons
• Definitionofdisease• Pre-clinicaldataquality• Publicationbias
• Waysforward• pRCTs• pre-clinicaltrials.org
http://pre-clinicaltrials.org orcamarades.info
Acknowledgements
Maastricht: Ana Casas, Vu Thao-Vi Dao, Vasco Gonçalves, Mahmoud Elbatreek, Ahmed Hassan, Jet Bost, Peter Lijnen, Pamela Kleikers
Melbourne: Karin Jandeleit-Dahm, Mark Cooper, Jennifer Wilkinson-Berka
Essen: Christoph Kleinschnitz, Friederike Langhauser, Eva Göb
Nijmegen: Merel Ritskes-Hoitinga, Carlijn Hooijmans
Madrid: Manuela Garcia Lopez
Boston/Barcelona/Vienna: Albert-László Barabási, Emre Guney, Jörg Menche
Advanced Investigator GrantProof of concept Grant