PERSONALIZED

MEDICINE

A Definition of Personalized Medicine

2

Personalized medicine is the use

information from a patient's genotype to:

of

initiate a preventative measure against the development

of a disease or condition, or
select the most appropriate therapy for a disease or
condition that is particularly suited to that patient.

Definition paraphrased from www.wikipedia.org

Other sources: Jones, D. Nature Reviews Drug Discovery 2007; 6:770-771; Katsanis et al. Science
2008; 320(5872):53-54; Feero et al. JAMA 2008; 299(11):1351-1352

Personalized Medicine
The ability to offer
The Right Drug
To The Right Patient
For The Right Disease
At The Right Time
With The Right Dosage
Genetic and metabolic data
will allow drugs to be
tailored to patient
subgroups

Personalized medicine takes into account individual

genetic differences
Traditionally, doctors used:

Family history
Socioeconomic circumstances
Environmental factors

Now:

genomic/genetic testing
proteomic profiling
metabolomic analysis (study metabolites)

Effectiveness of drugs:

Danger of drugs:
6.7% of patients in hospitals experience serious drug

reactions

Old Paradigm:

New Paradigm:

Future Paradigm:

Personalized Medicine Today

Genotypes and Human Disease

11

Do all humans have the same DNA?

What are single nucleotide polymorphisms

or SNPs?
Can we associate SNPs with medical

histories of individuals and achieve

statistically significant correlations?

SNPs a major source of variation

Single Nucleotide Polymorphisms

(SNPs)

A
A

Single base change in DNA. AAGCCTA

,AAGCTTA.

Most Common

SNP

A
SNPs arise as a consequence of mistakes
during normal DNA replication
Average frequency 1/1000

Deletion

Insertion

Other sources of variation

Insertions, deletions, translocation,

duplications, repeats

Translocation

The Diagnostic Industry

13

Companies are currently marketing test kits.

Saliva samples are tested and reports are sent to
the consumer.
Reports are based accepted clinical genetic
associations with risk but can also be obtained for
research without demonstrated association with
risk.

The Debate on Direct-to-Consumer Tests

14

Pros
Early warning about predisposition could promote

healthier lifestyles
Better patient confidentiality

Cons
Commercialization is testing really necessary?
Lacks regulation that would ensure accurate risk

assessments
Is the data more harmful than helpful without
context?
Is it beneficial to be informed that you are at high
risk to develop a disease for which there is no cure?
Testing of third parties and their privacy
Source: Howard et al. Future Medicine 2008; 5(4):317-320

Public Policy and Personalized Medicine

15

Genetic Information Nondiscrimination

Act of 2008 (H.R. 493, S.358)

Senator (now President-elect) Barack

Obamas Genomics and Personalized

Medicine Act of 2007 (S.976)

DHHS Secretarys Advisory Committee

on Genetics Health and Society

(SACGHS)

Sources: www.govtrack.us and Qureshi et al. Future Medicine 2008; 5(4):311-316

Gene Sequencing / Testing

RFLP analysis (restriction fragment length polymorphism)
SNPs (single nucleotide polymorphisms)

More than 1.4 million SNPs were identified in the initial

sequencing of the human genome, with over 60,000 of
them in the coding region of genes (Evans and McLeod
2003).

(but even silent mutations can affect phenotype)

Pharmacogenetics
Study of genetic variation that gives rise to

different responses to drugs

It is estimated that genetics can account for
20 to 95 percent of variability in drug
disposition and effects.
Nongenetic factors include: age, organ
function, concomitant therapy, drug
interactions, and the nature of the disease.

Pharmacogenomics
Better medication choices

100,000 Americans die annually and 2,000,000+ are

hospitalized due to adverse reactions to medications
Predict individual reactions to dugs

Safer dosing options

More exact dosing, optimum result/side effect balance

Improvements in drug development

Exclude genetic variations from certain clinical trials, speeding

up drug design time

Polygenic Determinants of Drug

Response
Differences in drug
sensitivity and renal
clearance

http://content.nejm.org/cgi/content/full/348/
6/538

Nine possible
combinations of drugmetabolism and drugreceptor genotypes and
the corresponding drugresponse phenotypes.
Each yields a different
therapeutic index
(efficacy:toxicity ratios)
ranging from 13 (65
percent:5 percent) to
0.125 (10 percent:80
percent).

Proteomic Profiling
Relevant in the identification and predisposition to

disease
Joshs presentation.

Metabolomic Analysis
First from urine analysis
Networks of metabolite feedback pathways

regulate gene and protein expression.

Metabolites also can mediate signalling
between organisms.
Biomarkers of disease (diagnostics)
The metabolome is therefore most predictive
of phenotype (Fiehn 2002; Weckwerth 2003).
However, an understanding of the resulting
data is limited owing to a fundamental lack of
biochemical and physiological knowledge
about network organization

Metabolomic Analysis
Metabolite
target
analysis

Metabolic
profiling

Metabolomi
cs

group of
all
metabolites, i.e
metabolites,
those associated
present in a
with a specific
cell or sample.
pathway.
Comprehensiv
Extraction
e
method (capillary
analysis of
electrophoresis,
gas or liquid
entire
chromatography)
metabolome
specially
under a given
designed for
set of
compounds in
conditions.
class to eliminate
unwanted/
irrelevant
http://swift.cmbi.ru.nl/euroschool/meta_seminar
metabolites.

focus on
one specific
metabolite

1.pdf

Metabolite
fingerprintin
g
the intention
is not to
identify each
observed
compound but
to
compare
patterns or
fingerprints of
metabolites
that change in
response to
disease or
toxin
exposure. Use
statistical

Applications of Personalized
Medicine
SOME BRIEF CASE STUDIES

 Cytochrome P450 genotyping test

Enzyme group cytochrome P450
Many types of medications(including antidepressents, anticoagulants,
proton pump inhibitors, etc)
Determine dosing and effects of these drugs.
Thiopurine methyltransferase test
Thiopurine
Thiopurine methyltransferase (TPMT)
UGT1A1 TA repeat genotype test
Irinotecan (Camptosar)
UGT1A1 enzyme
Dihydropyrimidine dehydrogenase test
5-flourouracil (5-FU)
Dihydropyrimidine dehydrogenase enzyme
Responsible for breaking down 5-FU

Uses in Muscular Dystrophy:

Becker and Duchenne MD same family of disease;

Duchennes more severe than Beckers because

generally the reading frame is preserved in BMD
while it is not in DMD.
DMD death around age 20; BMD life expectancy
may be reduced, but some have a normal life span.
Severity partially depends on mutation.
Dystrophin is the largest known gene in the human
body, located on the X chromosome.
79 exons
~15% caused by premature
stop codons
Phenotype-genotype
correlation studies

Gentamicin treatment in
DMD/BMD
Aminoglycoside antibiotic synthesized by Micromonospora
Works by binding the 30S subunit (inhibition site) of the

bacterial ribosome, interrupting protein synthesis (stop

codon readthrough)

Gentamicin treatment of Duchenne and Becker

muscular dystrophy due to nonsense mutations.
(Wagner et al 2001)
Some success in mouse model suppressed truncation of
protein and improved phenotype.
Cons: highly nephrotoxic; can have psychiatric side effects.

Irinotecan
Treatment for cancer that works by

inhibiting topoisomerase 1, which prevents

DNA from unwinding.
Clinical studies have revealed significant
associations between UGT1A1*28 and
irinotecan toxicity.
A recommended strategy for irinotecan-dose
adjustments based on individual genetic
factors has not yet been fully established.

Selzentry (Pfizer)
CCR5-tropic HIV treatment (CD4 immune cells)
Ineffective for CXCR4-tropic strains of HIV
profile assay to determine patients strain of HIV

Detect virus that does not act through CCR5 at levels as low as
0.3% of a viral population

Clinical trial patients selected with profile assay

The Food and Drug Administration, in a harbinger

of likely future actions, has just approved a drugdiagnostic combination for AIDS patients who are
running out of treatment options the hallmark of
personalized medicine.

Edward Abrahams
Personalized Medicine Coalition, 2007

Benefits of Personalized Medicine

Better matching patients to drugs instead of trial and

error
Customized pharmaceuticals may eliminate life-

threatening adverse reactions

Reduce costs of clinical trials by

Quickly identifying total failures

Favourable responses for particular backgrounds

Improved efficacy of drugs

The End
OR IS IT JUST THE BEGINNING?...