Impact of Genomics on the Diagnosis and Treatment of Disease

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Impact of Genomics on the Diagnosis and Treatment
of Disease
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Objectives

• What is genomics?
• How will genomics influence medicine?
• Where will genomics first have an impact?

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Some definitions

• Genomics
• Proteomics
• Functional Genomics
• Microarrays
• SNPs
• Bioinformatics

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What is a gene?

• Open reading frames
• Intron/Exon structure (alternative splicing)
• Gene regulation (promoters)
• The Central Dogma

Demo
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What did the human genome sequence reveal?

• Estimated number of genes (24,000 to 40,000)
• Estimated number of proteins (30,000 to 100,000)
• Chromosomal organization
• Repeat elements
• Disease genes

Slide 14 Genomics
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The promise of genomics

• New therapeutic agents
• New diagnostics
• New drug targets
• Shorten drug development cycle
• Personalized medicine

Demo
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Genomics will provide new Therapeutic Agents

• Promise
• Genes (human gene therapy)
• Antibodies (humanized and human antibodies)
• Proteins (chimeric and full length)

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Genomics will provide new Therapeutic Agents

• Issues
• Safety, production, immune response
• Protein, antibody turnover
• Production costs
• Drug delivery issues
• Humanizing/Human antibodies etc.

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Genomics will provide new Diagnostics

• Promise
• Every new gene provides three potential
  diagnostic reagents
• -Genes (hundreds of assays)
• -Antibodies (Westerns, ELISAs)
• -Proteins (Westerns, ELISAs)
• Microarrays will allow large scale diagnostics

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Genomics will provide new Diagnostics

• Issues
• Not all genetic testing straight forward (eg CF)
• Genomics by itself may not be very
  usefulfunctional genomics and proteomics needed?

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Genomics will provide new Drug Targets

• Promise
• More targets for Combichem
• Targets for structural genomics and in silico
  drug design
• Microbial targets for new antibiotics and
  anti-bacterial
• More disease genes/targets (e.g Gleevec)

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Genomics will provide new Drug Targets

• Issues
• How many new targets (500 vs 10,000s)?
• Are all proteins equally good targets?
• Will cost really go down?
• Genome Sequence revealed no new
  cyclins-implications for finding new disease
  genes.

HUMAN GENOME PROJECT TO SPARK EXPONENTIAL GROWTH
IN NUMBER OF TARGETS FOR DRUG INNOVATION
Number of Drug Targets (000s)
Source Drews,Jurgen,M.D.,Genomic Sciences and
the Medicine of Tomorrow Commentary on Drug
Development, Nature Biotechnology,
Vol.14,November 1996.
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Genomics will shorten the drug development process

• Toxicogenomics
• Pharmacogenomics
• -Patient selection
• -Target selection (protein variants)
• -Drug rescue

Demo
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Principles of Pharmacogenomics
SNP
Human DNA
Location of SNPs
Patients with efficacy in clinical
trials Patients without efficacy in clinical
trials Predictive of efficacy Predictive of no
efficacy
Source Pharmacogenetics and the practice of
medicine by Dr. Allen Roses Nature Vol 405 15
June 2000
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Potential of Pharmacogenomics
Genetic testing
Pharmacogenetics Medicine response profiles
Disease genetics Disease prognostics/diagnostics
Utility
Rare medelian diseases causal genes
Common complex diseases susceptibility genes
Genes for drug metabolism and/or action
SNP profiles for drug metabolism
What is tested
New disease insights and future medicines
Optimal medicine response
Benefits
Potential for family/unsolicited information
and ethical, legal and social implications
Risks
Source Pharmacogenetics and the practice of
medicine by Dr. Allen Roses Nature Vol 405 15
June 2000
16
Patient Selection
Non-responsive profiles define unmet need
Research
Abbreviated SNP linkage disequilibrium profile
for efficacy and common adverse events
Phase II clinical trials
Used to select patients for phase III clinical
trials
Smaller, faster and more efficient phase III
studies
Abbreviated SNP linkage disequilibrium profile
for serious, rare adverse events
Market approval with medicine response profile
pharmacogenetic surveillance
Comprehensive medicine response profile to
predict efficacy and adverse events
Enhancement with comprehensive medicine response
profile traditional surveillance
Source Pharmacogenetics and the practice of
medicine by Dr. Allen Roses Nature Vol 405 15
June 2000
17
Pharmacogenomics

• Genes involved in drug metabolism
• --Cytochrome p450 Over 60 of all drugs are
  metabolized by cycp450 There are over 20 alleles
  for this gene.
• --Defect in CYP2D6 gene leads to poor metabolism
  in 1/4 of all drugs, including many
  antipsychotics and cardiac drugs
• --Variation in N-acetyltransferases (NAT1 and
  NAT2) leads to slow acetylation and toxicity of
  drugs including isniazind, phenelzine, and
  procainamide
• Disease related genes with known variants
  BRCA1/2 (breast cancer)apoE2, apoE3, apoE4
  (Alzheimers)

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Potential of Pharmacogenomics
Genetic testing
Pharmacogenetics Medicine response profiles
Disease genetics Disease prognostics/diagnostics
Utility
Rare medelian diseases causal genes
Common complex diseases susceptibility genes
Genes for drug metabolism and/or action
SNP profiles for drug metabolism
What is tested
New disease insights and future medicines
Optimal medicine response
Benefits
Potential for family/unsolicited information
and ethical, legal and social implications
Risks
Source Pharmacogenetics and the practice of
medicine by Dr. Allen Roses Nature Vol 405 15
June 2000
19
Target Selection
Discovery Genetics
Genetically validated target
Gene variants identified as associated with
disease susceptibility
Focused use of functional genomic technologies
Gene variant-specific metabolic differences
Gene-derived target for screening
Not a target
Discovery Genomics
Screening use of functional genomic technologies
Sequence-selected gene collections (for example,
nuclear receptors, proteases and kinases)
Human genome sequence
Favored validated gene-derived targets for
screening
Hypotheses nominated or candidate genes
Source Pharmacogenetics and the practice of
medicine by Dr. Allen Roses Nature Vol 405 15
June 2000
20
Pharmacogenomics

• Identifying responders (patients who will benefit
  from a drug) through target genotyping
• --Genotyping of ß2-adrenergic receptor
• --Allows selection of optimal therapy for heart
  failure and asthma treatment
• Liggett SB, Pharmacogenetics of beta-1 and
  beta-2-adrenergic receptors, Pharmacology 1999
  Sep 61(3)167-73
• Identifying non-responders through target
  genotyping
• --Genotyping of 5-hydroxytryptamine (5-HT2A)
  serotonin receptor
• --Identifies patients non-responsive to clozapine
  (anti-psychotic)
• Kleyn and Vessel, Genetic Variation as a Guide
  to Drug Development, Science, 1998,
  281820-1821.
• Drug rescue
•     --Seldane (allergies) causes arrhythmia when
  prescribed with antibiotics in lt10 of patients.

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Pharmacogenomics

• Issues
• Rationale
• Challenges
• Timelines for implementation
• Costs--can we really map enough SNPs in enough
  people cheaply?

Technology requirements
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Mapping SNPs

• Numbers of SNPs to be mapped is very large
• Assay becomes very important (few cents/SNP)
• CompaniesThird Wave, Qiagen, ABI, Pyrosequence
  etc.

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Personalized medicine

• Gene databanks
• Genetic counseling
• First Genetic Trust, DNA Sciences, Genome Health,
  GeneSage, DeCode, Hibernia..
• Issues Privacy/Approach

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Summary

• Genomics will fundamentally alter how medicine
  is practiced. These changes will first be seen
  in the realm of diagnostics, but will eventually
  involve new therapies and the era of personalized
  medicine

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GeneEd courses

• 101
• BioPharma Basics
• Human Gene Therapy
• Combinatorial Chemistry
• Computer Assisted Drug Design
• Immunity and Disease
• Genomics
• Anti-HIV Therapies

• 201
• Methods in Molecular Biology
• Microarrays
• SNPs Identification and Uses
• Bioinformatics