Transcript Personalized_Medicine

PERSONALIZED MEDICINE
JA M ES W E I S A N D L I LY C H A N
Personalized medicine takes into account individual genetic
differences
 Traditionally, doctors used:
Family history
 Socioeconomic circumstances
 Environmental factors
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 Now:
genomic/genetic testing
 proteomic profiling
 metabolomic analysis (study metabolites)
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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
The Plan
The Plan:
The Plan:
IT/CS Challenges
Medical
Challenges
Biological Challenges
Engineering Challenges
P.M.
Breather…
(WHEW)
Gene Sequencing / Testing
 RFLP analysis
 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).
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(but even silent mutations can affect phenotype)
The accuracy of DTC genome-scan tests has been questioned, but
Venter et al. found that the genotypes, or particular DNA bases
observed, of an individual’s markers from 23andMe and Navigenics
agreed more than 99.7% of the time. Same for most other tests.
What the tests do disagree on, however, is the
disease risk…
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Do predicted disease risks have any clinical validity?
Genotype-phenotype correlation?
Certain disease risks can be better predicted than others.
Pharmacogenomics
DOES ONE SIZE REALLY FIT ALL?
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 – Under the PM Umbrella
 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
Nine possible combinations
of drug-metabolism and
drug-receptor 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).
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 signaling 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
focus on one
specific
metabolite
Metabolic
profiling
group of metabolites,
i.e those associated
with a specific
pathway.
Extraction method
(capillary
electrophoresis, gas
or liquid
chromatography)
specially designed for
compounds in class to
eliminate
unwanted/ irrelevant
metabolites.
http://swift.cmbi.ru.nl/euroschool/meta_seminar1.pdf
Metabolomics
all metabolites,
present in a cell or
sample.
Comprehensive
analysis of entire
metabolome
under a given set
of conditions.
Metabolite
fingerprinting
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 tools to
look for major
differences.
static
dynamic
Applications of Personalized
Medicine
SOME BRIEF CASE STUDIES
Personalized medicine today yesterday
 Cytochrome P450 genotyping test
 Enzyme group ‘cytochrome P450’ (CYP450
 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
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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 mdx mouse model – suppressed truncation of
protein and improved phenotype.
 Cons: highly nephrotoxic; can have psychiatric side effects.
Ataluren (PTC-124) and PRO051
 Mutation specific
 Both aim to restore reading frame:
 Ataluren does this through ribosomal stop codon readthrough
 PRO051 does this through exon skipping (block splicing machinery)
Duchenne  Becker phenotype
Ataluren mechanism
•Nonsense mutations
result in a premature stop
codon (UAG, UAA, or
UGA) and cause a
truncated protein.
•Works best on UGA stop
codon.
Concept applicable to other diseases that also result from
nonsense mutations, such as cystic fibrosis and nonsensemutation hemophilia A and B (nmHA/B).
 As mentioned before, only ~15% have nonsense
mutations. Others have deletions, inversions,
insertions, point mutations that do not result in a stop
codon…
 Many specific sequences will be required for effectively
treating the majority of patients with DMD. Will each
specific sequence need to go through full testing
required by the Food and Drug Administration (FDA)?
 Toxicity standards?
Analysis of Dystrophin Deletion Mutations Predicts Age of
Cardiomyopathy Onset in Becker Muscular Dystrophy
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
 Trofile ™ 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 Trofile ™ 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
The End
OR IS IT JUST THE BEGINNING?...