PERSONALIZED MEDICINE

JAMES WEIS AND LILY CHAN

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

The Plan

The Plan:

The Plan:

IT/CS Challenges

Medical Challenges

Biological Challenges

Engineering Challenges

P.M.

(WHEW)

Breather…

Gene Sequencing / Testing

RFLP analysisSNPs (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)

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.

Do predicted disease risks have any clinical validity? Genotype-phenotype correlation?

Certain disease risks can be better predicted than others.

What the tests do disagree on, however, is the disease risk…

DOES ONE SIZE REALLY FIT ALL?

Pharmacogenomics

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

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).

Differences in drug sensitivity and renal clearance

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 analysisNetworks 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…”

Metabolite target analysis

Metabolic profiling

Metabolomics Metabolite fingerprinting

all metabolites, present in a cell or sample. Comprehensiveanalysis of entire metabolome under a given set of conditions.

the intention is not to identify each observed compound but tocompare patterns or fingerprints ofmetabolites that change in response to disease or toxin exposure. Use statistical tools to look for major differences.

focus on one specific metabolite

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 eliminateunwanted/ irrelevant metabolites.

http://swift.cmbi.ru.nl/euroschool/meta_seminar1.pdf

Metabolomic Analysis

static dynamic

SOME BRIEF CASE STUDIES

Applications of Personalized Medicine

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 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 codonsPhenotype-genotype

correlation studies

Gentamicin treatment in DMD/BMD

Aminoglycoside antibiotic synthesized by MicromonosporaWorks 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 specificBoth 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

•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 nonsense-mutation hemophilia A and B (nmHA/B).

Ataluren mechanism

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 HIVTrofile ™ 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 drug-diagnostic combination for AIDS patients who are running out of treatment options … the hallmark of

personalized medicine.”Edward Abrahams

Personalized Medicine Coalition, 2007

OR IS IT JUST THE BEGINNING?...

The End