principles of translational medicine: relationship between...
TRANSCRIPT
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Principles of Translational Medicine:
relationship between animal and
human pharmacology
Compiled by: Endre Mikus PhD, CEO
Budapest, 21/10/2017
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.2
Outline
Definitions
Pre-Translation Medicine
Early Translational Medicine
Trends in recent Translational Medicine
Examples
Special aspects of biologics
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Translational Medicine
Definition
„There is no clear definition of
translational medicine; it means
different things to different people.”
https://www.eupati.eu/non-clinical-
studies/translational-medicine/
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.4
Translational Medicine
Definition
„funding priorities that
emphasized multi-
disciplinary and trans-
disciplinary approaches
to translating discoveries
in one research paradigm
to another, ultimately
leading to improved
health outcomes.”
http://mscti.med.miami.edu/program/what-is-translational-research/
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Pre-Translational Medicine
.5
efficacysafety
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Pre-Translational Medicine
Treat the symptoms with new drugs
Few disciplines: basic/applied/clinical
science not separated
Few and symptom similar animal models
Simple human trials
Not too much emphasis on toxicology
Easy registration
.6
Disease=symptoms
R&D
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The similarity in biology and symptoms
between the animal model and the human
disease.
The preclinical animal models predict
well drug effect on human:
Efficacy
Side effects/unwanted effects
Toxic effect.7
Old „paradigm” of pharmacology
„An animal sufficiently like humans…”
Assumption
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Only few players e.g. doctors, chemists
Few disciplines
Common language, easy communication
Simple organisation chart
Low cost high return
.8
Original PlayersPre-Translational Medicine
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Outcome
New, effective natural origin
and synthetic drugs
.9
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Everybody was quite
happy with the
outcome. Until...
.10
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A bit later on...
Turned out
Efficacy is not enough
Safety is first
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More tests and More investment
More disciplines More players
No more common language
Difficult communication
Concomitant
Serious cost increase in drug R&D
and hight attrition rate
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.13 https://books.google.hu/books?id=fNMcCwAAQBAJ&pg=PA9&lpg=PA9&dq=drug+r%26d+disciplines+1960&source=bl&ots=IjMMzjgX-
y&sig=taA7ByYFJSy1hkHFLXvip5hk18U&hl=hu&sa=X&ved=0ahUKEwiv4ei4143XAhXJblAKHdFmC_MQ6AEIRjAG#v=onepage&q=drug%20r%26d%20disciplines%201960&f=false
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HELP!
Something was needed to help the
communication among disciplines and to
support the integration of the new
achivements of basic science into clinical
practice.
The Translational Medicine was
born
.14
„The term translational medicine was introduced
in the 1990s but only gained wide usage in the
early 2000s.” https://www.britannica.com/topic/translational-medicine
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Early Translational Medicine
.15
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Early Translational Medicine
.16
„The preclinical animal models
predict well drug effect on human”:
Efficacy
Side effects/unwanted effects
Toxic effect
No real paradigm change
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Early Translational Medicine
.17
http://www.technewsdaily.com/4979-nih-translational-center-pharmaceutical-drugs-innovation.html
„I feel the tremor
in the force”
High attrition rate in drug R&D
Increasing development costs
Decreasing FDA approvalsPrice of drugs
STILL
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.18
Reasons for failure
http://www.nature.com/nrd/journal/v15/n12/full/nrd.2016.184.html?foxtrotcallback=true
The pre-clinical models/approaches were not
appropriate in respect of human use
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.19
CONCLUSION
WANTED because of the predictive value of his pharmacology models is approching to the zero
“Currently, nine out of ten
experimental drugs fail in
clinical studies because we
cannot accurately predict how
they will behave in people
based on laboratory and
animal studies.”http://cdn.intechopen.com/pdfs/42018/InTech-
Animal_models_in_drug_development.pdf
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Significant differences
FACTORS HUMAN EXPERIMENTAL ANIMAL
Genetic background Heterogeneous, outbred,
races
Homogeneous, inbred, strains
Environment Diverse, full of stress,
pollutions, seasons
etc.
Well balanced, no stress, cleaned air,
standard temperature and
humidity, specific pathogen free
conditions
Food and beverages Different, complex Rodent chow, cleaned water
Age, scenescence Wide range Usualy young
Sex Both One of them preferred
Chronic disease
progression
Generaly low Accelerated
Disease phenotype Diverse Homogeneous
Origin of the disease Natural Arteficial
Anatomy/physiology Human Rodent
Treatment schedule Usually curative Usually preventive
Placebo/nocebo effect Significant Missing
Ortolog differences
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.21
Animal model scepticism
„Reuters quoted Francis Collins, Director of the NIH, as stating that:
“about half of drugs that work in animals may turn out to be toxic for
people. And some drugs may in fact work in people even if they fail
in animals, meaning potentially important medicines could be
rejected.”
http://cdn.intechopen.com/pdfs/42018/InTech-Animal_models_in_drug_development.pdf
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.22
Don’t mix!
Pharmacology animal model
Animal disease Human disease
Translational research helps in
differentation
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Conclusion
Something must be done
.23
Paradigm change is needed
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Trends in recent Translational
Medicine
.24
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Rational drug R&D strategy is
needed...
We still don’t know enough about the human
molecular pathology.
We still don’t know enough about the
pharmacology animal model molecular
pathology.
.25
Solution: we must increase our knowledge
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Efficacious implementation of the achievements
of basic science to healthcare
Understand better the diseases
Understand better the animal models
Use the most appropriate animal models
Improve the communication among the disciplines
Decrease high attrition rate
Shorten development time
Predict early Succes/Failure
Patient stratification
Apply biomarkers; pre-clinical and clinical
.26
Tasks of recent Translational
Medicine
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New paradigm of drug R&D
Interact into the molecular
pathomechanism with new tools
.27
Disease not only symptom
Molecular pathomechanism
Omic associations
Deeper information and better
understanding
The dark side of the drugs
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.28
We are not identical
„An animal sufficiently like
humans…” Not true
Pharmacology paradigm
change
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The grandiose recognition
We are not identical
.29
Recognition of patients
heterogeneity
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.30
„An animal sufficiently like
humans…” Not true
„Consequently, an animal model or a human
disease is by no means attempting to reproduce
the human disease with all its complexities in an
animal but rather to model specific aspects of a
disease.”
„Whenever using an animal model, it is thus of
utmost importance to define a specific question
and to ensure that the chosen model is fit-for-
purpose. „
NewHorizonsinTranslationalMedicine2(2014)5–11
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Hypothesis
The predictive value of the animal models can be
increased by enriching our knowledge on the
molecular pathomechanism of human disorder and
preclinical animal models.
Knowing what molecular mechanism does make the
difference among the patient subgroups.
If the molecular pathomechanism is known and we
could find animal model where the same pathway in
the same way is impaired the predictive value would
increase.
However, it will not help „Commercial and Strategy”
failures. .31
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New preclinical pharmacology
paradigm
Face validity: The similarity in biology and symptoms
between the animal model and the human disease.
Predictive validity: Demonstration that clinically
effective interventions demonstrate a similar effect in the
model.
Target validity: The target under investigation should
have a similar role in the disease model as in the clinical
situation. One classical example is the beta-3 adrenergic
receptor which has an important role in the energy
metabolism of rodents but not in humans.
.32 NewHorizonsinTranslationalMedicine2(2014)5–11
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.33 NewHorizonsinTranslationalMedicine2(2014)5–11
Animal model validity scoring
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https://www.fda.gov/drugs/developmentapprovalprocess/drugdevelopmenttoolsqualificationprogram/ucm284078.htm
Quality in specific pharmacology
Voluntary, GLP regulations
„For the purpose of this guidance, an animal
model is defined as a specific combination of an
animal species, challenge agent, and route of
exposure that produces a disease process or
pathological condition that in multiple important
aspects corresponds to the human disease or
condition of interest.”
.34
FDA:Animal Model Qualification
Program
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/UCM230597.pdf
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.35
ExampleSmall molecular weight
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.36 https://www.frontiersin.org/articles/10.3389/fimmu.2015.00551/full
Inflammatory Bowel Disease
example
Genotype-Phenotype
AIM1. Better understanding of the molecular
pathomechanism
2. Development of new drugs and diagnostic tools
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.37
Inflammatory Bowel Disease
ExampleSearching for susceptibility genes and
associated molecular mechanisms
Genom Wide Association Studies (GWAS)Study specific genes with some overlapping with other study hits
The function of severeal genes are unknown
Few druggable targets
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.38
Inflammatory Bowel Disease
Example
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.39 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314302/
Drugs are categorized based on the mechanism of action.
Purple symbols indicate oral drugs.
IL, interleukin; TNF, tumor necrosis factor.
The therapeutic pipeline in ulcerative
colitis (UC)
The therapeutic pipeline in Crohn’s
disease (CD)
Inflammatory Bowel Disease
Példa
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.40 http://www.cmghjournal.org/article/S2352-345X(15)00040-5/pdf
Most frequently used IBD animal
models
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.41
Genomics of IBD animal models
Comparison of the gene experession profile of different IBD animal models.
32 known IBD successibility genes:TNF, IFN-, Lt, IL-6, IL-16, IL-18R1, IL-22,
CCR2, 7, CCL2, 3, 4, 5, 7, 11, 17, 20, CXCR3, CXCL1, 5, 10, Mmp3, 7,9, 14,
Timp1, Reg3, and Pap, S-100a8, S-100a9, Abcb1, and Ptgs2
2/32 upregulated genes in TNBS model
15/32 upregulated or downregulated in DSS model
30/32 are upregulated or downregulated in CD45RB transfer colitis model
Inflamm Bowel Dis 2007, 13:325-330
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.42 Inflamm Bowel Dis
. 2009 June ; 15(6): 890–899
Gene expressin in
IL10-/- mice IBD model
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.43
Venn diagram illustration of gene expression similarity between DSS-induced colitis and ulcerative colitis (UC)
patient sample microarray data. A: 944 genes were upregulated at day 6 in DSS colitis compared with 876
upregulated genes from UC patients; 152 of these genes were similarly upregulated between both data sets. B: 665
genes were downregulated at day 6 during DSS colitis compared with 267 downregulated genes from UC patients;
22 of these genes were similarly downregulated between both data sets.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026350/
Gene expressin in
DSS colitis model
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.44
Genes in the
pharmacology model
Susceptibility genes and
mechanisms in human diseases
Model 1
Model 2
Model 3
Model 4
-GWA studies
-other specific genomic
and/or omic approaches
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.45
Probably
high
predicted
value model
Model 1
Model 2
Model 3
Model 4
Genes in the
pharmacology modelSusceptibility genes and
Mechanisms in human diseases
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.46
Translational Medicine
Imaging
https://www.liverpool.ac.uk/translational-medicine/research/centre-for-preclinical-imaging/msot/
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Rodent colonoscopy
DSS colitis model
Analogue with human biomarker
Biopsy option
Do not need to exterminate the animals; model progression
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1774595/pdf/gut05400950.pdf
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cHS4I-hIL-1βP-Luc transgenic mice
Interleukin 1 beta (IL-1β)
contributes to the
development of
inflammatory bowel
disease (IBD) and is
correlated with the severity
of intestinal inflammation.
https://journal-inflammation.biomedcentral.com/track/pdf/10.1186/1476-9255-10-
16?site=journal-inflammation.biomedcentral.com
Rodent DSS colitis model
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.49 https://www.researchgate.net/publication/282036993_CD4_T_cells_are_required_for_both_development_and_
maintenance_of_disease_in_a_new_mouse_model_of_reversible_colitis
Rodent colonoscopy
CD4+ transfer colitis model
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.50 http://parts.igem.org/Part:BBa_K1993009
Rodent TNBS colitis model
MSC-mesenchymal stem cell
Homing efficiency of MSCs and illustrating their
distribution
Under IVIS Spectrum, MSCsCXCR4 exhibited enhanced capacities for targeted
migration to the bowels in IBD model.
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.51https://www.researchgate.net/publication/287126056_Histamine_H2_Receptor-
Mediated_Suppression_of_Intestinal_Inflammation_by_Probiotic_Lactobacillus_reuteri/figures?lo=1
Rodent imaging
TNBS colitis model
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.52
Magnetic Resonance Imaging (MRI)
for mice
Magnetic resonance imaging is a radiological
tool used in the diagnosis of internal diseases in
soft tissue, such as the brain and heart.
http://www.mouseimaging.ca/technologies/mri.html
The 7-T, 40-cm MRI used to image multiple mice.
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Micro-Computed Tomography (micro-CT)
for miceHigh-resolution X-ray computed tomography produces detailed three-dimensional images of soft tissue and bone structure. In the case of soft tissue, the highest resolutions are achieved with the help of a contrast agent, which increases the X-ray attenuation of the tissue of interest
Liver of mice vasculature
http://www.mouseimaging.ca/technologies/microct.html http://openi.nlm.nih.gov/detailedresult.php?img=3095598_pone.0019389.g004&req=4
bone-metastases
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Single photon emission computed tomography - computed
tomography (SPECT-CT) imaging for mice
The primary use of the facility is for the development and validation of novel radiolabeled imaging ligands which can be used for tumor detection, cell tracking, diagnosis of autoimmune diseases or vulnerable plaque localization.
https://csb.mgh.harvard.edu/mouse_imaging/spect-ct
The system can be used with various isotopes, most
frequently 111In and 99mTc. The spatial resolution for the
SPECT system is approximately 1 mm.
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Translational Medicine links to
Systems Pharmacology
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Translational medicine, special issues to be
addressed in the non-clinical development of
biological medicinal agents
Compiled by: Endre Mikus PhD, CEO
Budapest, 14/10/2017
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Expected translational flowchart
„classical flowchart”
.57
Molecular target and drug
candidate interaction
ResponseThe structure of molecular target
is species dependent
Rodent
Human
Specific Pharmacology (therapeutic)
Safety pharmacology (side effects)
Toxicology
Biosimilar tests
human 100
dog 88 100
sheep 84 86 100
rabbit 76 77 75 100
mice 73 72 76 66 100
rat 72 72 72 68 89 100
guinea
pig
75 76 72 72 74 72 100
human dog sheep rabbit mice rat guinea
pig
The molecule under development interacts with both
human and rodent orthologue targets.
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Challenge of Translational Medicine
Gap in the „classical” flowchart
.58
Molecular target and drug
candidate NO interaction
ResponseThe structure of molecular target
is species dependent
Rodent
Human
Specific Pharmacology (therapeutic)
Safety pharmacology (side effects)
Toxicology
Biosimilar tests
The molecule under development does not interact with
rodent orthologue target.
The molecule is human specific.
?
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SOLUTION
Creation of arteficial systems
.59
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Working options 1/2
Searching for cross reacting animal species
Primate
Outbred , serious ethical considerations, expensive etc.
Only the 10% of the human specific antibodies show cross
reactivity with non-human homologue protein. Furthermore,
only the 10 % whithin this 10% show efficacy.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2759500/pdf/mabs0105_0505.pdf
Surrogate/homolgue antibodyAn animal specific antibody is used in a preclinical phase for
pharmacodynamic, pharmacokinetic and toxicology studies.
Human transgene animalsThe human targeted protein is expressed in the rodents. The
human protein substitutes the rodent orthologue.
.60
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Working options 2/2
Humanised mice
Immuno-compromised animals with working
human genes, cell, tissues or even organs.
.61
The Bicentennial Man
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Humanised mouse
Both human and mouse immune cells are
present at the same time in the animals (!/?).
.62
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ISSUE
Immunogenicity if Biologics
Anti-drug antibodies (ADA) are produced during
protein therapy.
Immunogenicity to biologics represents a
significant hurdle in the continuing therapy of
patients in a number of disease settings.
Consequences:
Continuous decrease of potency
Systemic allergic hyperrection
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Immunogenicity of Biologics
Immunogenicity
„Many biotechnology-derived pharmaceuticals
intended for humans are immunogenic in
animals.” Risk:underestimation safety and
toxicology concerns
„The induction of antibody formation in animals is
not predictive of a potential for antibody formation
in humans.”
.64 Guidance for Industry S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals
Relevant preclinical models
are needed
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Immunogenicity
Transgenic mice and xenograft
transplantation models have been generated.
.65
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.66
Thank you for your attention
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.67 http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2015000200096
Inflammatory Bowel Disease
Példa
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.68
Animal disease versus Pharmacology
animal model
Animal diseases occure when the animals
become ill. These illnesses can be similar to
human diseases, develop „spontaneously” and
can also be used for testing new chemical
entities.
Pharmacology animal model when scientists
make interventions on healthy animals to show
phenotypes similar to human diseases
Disease models
Mechanistic models
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Task of Translatinal research
Definitions of disease
DISEASE=Genetic predisposition+environmental factors
Genetic predisposition is an inherited risk of developing
a disease or condition.
DISEASE=NOT HEALTHY
Objective and subjective symptoms
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.70
Dis-integration
Disease phenotypes,
personalised medicine
Hourglass perspective of disease evolutionsympmtoms are not enough any more
Symptom+biomarker
Biomarker
Omics
Grouping
Asthma, COPD
Functional GI
disorders, etc.
DIAGNOSIS
Symptom
Pre-Translational
Translational
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.71
Not only phenotype matters
End of symptom hegemony
The Word of Biomarkers arrived?
http://basdai.com/research2.htm http://basdai.com/research2.htm
http://ocw.tufts.edu/Content/19/CourseHome/302560/302572
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Task of Translational research
Analysing problems making solutions
The new achivements of genomics, proteomics and
epigenetics have to be applied both in pre-clinical and
clinical pharmacology in order to syncronise preclinical
pharmacology with clinical trial protocols.
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BIOMARKERS
We need words
http://sciclips.wordpress.com/2012/01/09/cancer-theranostics-potential-applications-of-cancer-biomarker-database/
Biomarkers are the words
used by Translational
research
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"a characteristic that is objectively measured and
evaluated as an indicator of normal biologic
processes, pathogenic processes, or
pharmacologic responses to a therapeutic
intervention."
early diagnosis
patient stratification
and monitoring of treatment responses
The official NIH definition of a biomarker
Biomarkers in the bench and in the clinic
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.75 http://www.profactproteomics.com/services.html
Where do the biomarkers come from?
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.76 http://www.eusem.com/main/CH/pot
Omics
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Task of Translational research
Genotype-Phenotype relationships
Genomics
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Let we start with „easy”!
Gaucher’s disease
the genotypes are known
monogenic disorders
Genotype Phenotypes
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Gaucher’s disease
The mutation of a single gene induces several phenotypes
The disease arises due to genetic mutations. More than 300 genetic mutations have
been found to be associated with Gaucher’s disease.
Gaucher’s disease is a common lysosomal storage disease that results from inherited mutations in the gene encoding acid-glucosidase
http://www.sciencedirect.com/science/article/pii/S1096719204002240
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Glucocerebrosidase gene-deficient
mouse
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.81
Let we see a bit harder example!
Chronic obstructive pulmonary disease (COPD)
GenotypePhenotypes
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Genome-Wide Association Study…
…is an examination of many common genetic variants in different individuals to see if any variant is associated with a trait.
GWAS typically focus on associations between single-nucleotide polymorphisms (SNPs) and traits like major diseases.
GWAS
Better understanging
New tharepeutic targets
Patient subpopulations
Personalised medicine
Realionship among other
diseases
Biomarkers
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Several phenotypes
Diagnosis is based on pulmonary function
measurementsThe diagnosis of COPD is highly depending on which guidelines are
used for defining the disease (Respiratory Research 2007, 8:89)
Following 3887 individual spirometry study
10.2% fulfilled NICE COPD
14 % fulfiled GOLD COPD
21.7 % fulfilled ERS
Chronic obstructive pulmonary disease
(COPD)
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.84
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.85
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Genotype-Phenotype realtionship
Human
Studies of genotype–phenotype correlations
reveal significant genotypic heterogeneity
among clinically similar patients, and vastly
different phenotypes among patients with the
same mutations.
Increasing number of published GWAS studies
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169525/figure/pgen-1002269-g001/
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How the animal models could approach
to the human pathology?
Animal
models
Human
Pathology
Pharmacology model
development
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Animal diseases as potential
pharmacology models
Genomics in animals diseases
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Animal diseases as models for human
diseases
Noninsulin-dependent diabetes mellitus (NIDDM), with
mild obesity
Otsuka Long-Evans Tokushima Fatty (OLETF) rats
Chronic Obstructive Pulmonary Disease
Heaves on horses
Atopic Dermatitis
Canine atopic dermatitis in the West Highland White Terrier
Scott syndrome is a rare hereditary bleeding disorder
Canine Scott syndrome
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.90
Genomics in animal models
Comparison of the gene expression changes in experimental colitis models
Of 32 genes that are known to change transcriptional activity in IBD:TNF, IFN-,
Lt, IL-6, IL-16, IL-18R1, IL-22, CCR2, 7, CCL2, 3, 4, 5, 7, 11, 17, 20, CXCR3,
CXCL1, 5, 10, Mmp3, 7,9, 14, Timp1, Reg3, and Pap, S-100a8, S-100a9, Abcb1,
and Ptgs2
2/32 are upregulated in TNBS,
15/32 are upregulated or downregulated in DSS
30/32 are upregulated or downregulated in the CD45RB transfer colitis.
Inflamm Bowel Dis 2007, 13:325-330
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The genetic modification of laboratory
mouse strains produces quite homogeneous
genotype-phenotype relationship.
Genotype-Phenotype relationship
Genotype-Phenotype relationship
Animal
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nlm.nih.gov/pmc/
articles/PMC2692
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