Personalized Medicine

A Definition of Personalized Medicine

Personalized medicine is the use of information from a

patient's genotype to:
• 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

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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

• 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?

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 SNPs – a major source of variation
• Single Nucleotide Polymorphisms (SNPs)
– Single base change in DNA. AAGCCTA Most Common
,AAGCTTA.
A
A A SNP

– SNPs arise as a consequence of mistakes

during normal DNA replication
Deletion
– Average frequency 1/1000

Insertion
• Other sources of variation
– Insertions, deletions, translocation, duplications,
repeats
Translocation
 The Diagnostic Industry

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.

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The Debate on Direct-to-Consumer Tests

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

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Source: Howard et al. Future Medicine 2008; 5(4):317-320
Public Policy and Personalized Medicine

• Genetic Information Nondiscrimination Act

of 2008 (H.R. 493, S.358)
• Senator (now President-elect) Barack
Obama’s Genomics and Personalized
Medicine Act of 2007 (S.976)
• DHHS Secretary’s Advisory Committee on
Genetics Health and Society (SACGHS)

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

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 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
 Polygenic Determinants of Drug Response

Differences in drug sensitivity

and renal clearance

Nine possible combinations

of drug-metabolism and
drug-receptor genotypes and
the corresponding drug-
response phenotypes. Each
yields a different therapeutic
index (efficacy:toxicity ratios)
ranging from 13 (65 percent:5
percent) to 0.125 (10
percent:80 percent).

http://content.nejm.org/cgi/content/full/348/6/538
 Proteomic Profiling
• Relevant in the identification and
predisposition to disease
• Josh’s 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 Metabolic Metabolomics Metabolite

target analysis profiling fingerprinting

focus on one group of metabolites, all metabolites, the intention is

specific i.e those associated present in a cell or not to identify
with a specific sample. each observed
metabolite pathway.
Comprehensive compound but to
Extraction method compare patterns
(capillary analysis of entire
metabolome or fingerprints of
electrophoresis, gas
metabolites that
or liquid under a given set
change in
chromatography) of conditions.
specially designed for response to
compounds in class to disease or toxin
eliminate exposure. Use
unwanted/ irrelevant statistical tools to
metabolites. look for major
differences.
http://swift.cmbi.ru.nl/euroschool/meta_seminar1.pdf
Applications of Personalized
Medicine
Some brief case studies
 Personalized medicine

 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;

Duchenne’s more severe than Becker’s 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 drug-diagnostic
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?...