Genetic Discovery of Drug Targets <ul><li>Most drugs block the activity of proteins </li></ul><ul><li>Genetic models of dr...
Example 1: A Target for Osteoporosis <ul><li>Sclerosteosis: pathology due to growth of dense, strong bones </li></ul><ul><...
Genetic Mapping to 17q21 Shared Disease Haplotype in black Genetic mapping of 22 families  defined a region of chromosome ...
Candidate Gene Identification by Sequencing   (Circa 1997) <ul><li>Isolated a set of 30 clones that spanned 3 megabases </...
Functional Confirmation of Mutation <ul><li>Single base change in one gene  </li></ul><ul><li>Found a different change in ...
“ Sclerostin” is a Cystine Knot Protein <ul><li>Secreted protein that resembles BMP antagonists DAN and Noggin </li></ul><...
Patent on Antibodies That Block Sclerostin  <ul><li>We Claim: </li></ul><ul><li>1. A method for altering bone density comp...
Anti-Sclerostin Antibody in Clinical Trials
Example 2: Protective Allele in Crohn’s
IL23 Pathway as a Drug Development Target <ul><li>Loss-of-function alleles lead to reduced disease risk </li></ul><ul><li>...
IL-23 Antagonist in Clinical Trials This work pre-dated the genetic mapping results
“ Drug Surrogate” Mutations <ul><li>Discovery of the sclerosteosis mutations directly led to the development of a drug for...
Mapping Strategy <ul><li>Use clinical data and genealogy information to identify individuals and pedigrees </li></ul><ul><...
Examples <ul><li>Low or high lipid levels without disease </li></ul><ul><li>Fat taste sensitivity and BMI </li></ul><ul><l...
Changing the Economics of Drug Development <ul><li>The biggest cost of drug development is the cost of failure  </li></ul>...
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Human Genetics For Target Discovery

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Human Genetics For Target Discovery

  1. 1. Genetic Discovery of Drug Targets <ul><li>Most drugs block the activity of proteins </li></ul><ul><li>Genetic models of drugs (“Drug surrogates”) </li></ul><ul><ul><li>Protective alleles </li></ul></ul><ul><ul><li>Loss of function mutations that mimic desired drug activity (“drug surrogate mutations”) </li></ul></ul><ul><li>Genetically-identified targets are superior </li></ul><ul><ul><li>Strong proof of target validity- in humans </li></ul></ul><ul><ul><li>Significantly higher probability of success in clinical trials </li></ul></ul>
  2. 2. Example 1: A Target for Osteoporosis <ul><li>Sclerosteosis: pathology due to growth of dense, strong bones </li></ul><ul><li>Isolated population </li></ul><ul><li>Recessive mutation </li></ul><ul><ul><li>Loss of function </li></ul></ul>Normal Sclerosteosis
  3. 3. Genetic Mapping to 17q21 Shared Disease Haplotype in black Genetic mapping of 22 families defined a region of chromosome 17q21
  4. 4. Candidate Gene Identification by Sequencing (Circa 1997) <ul><li>Isolated a set of 30 clones that spanned 3 megabases </li></ul><ul><li>Identified 150 candidate genes </li></ul><ul><li>Sequenced the candidate genes in patients and controls </li></ul>
  5. 5. Functional Confirmation of Mutation <ul><li>Single base change in one gene </li></ul><ul><li>Found a different change in the same gene in a different population </li></ul><ul><li>Built four different versions of the genes to confirm that the mutations blocked its function </li></ul><ul><li>Two mutations were not present in 360 controls </li></ul>
  6. 6. “ Sclerostin” is a Cystine Knot Protein <ul><li>Secreted protein that resembles BMP antagonists DAN and Noggin </li></ul><ul><li>Part of the normal regulation of bone metabolism </li></ul><ul><li>Antibodies to Sclerostin can block its activity </li></ul><ul><li>Variations in the gene affect bone density in the general population </li></ul>Noggin protein (family member)
  7. 7. Patent on Antibodies That Block Sclerostin <ul><li>We Claim: </li></ul><ul><li>1. A method for altering bone density comprising administering to an individual a therapeutically effective amount of antibody that binds to (sclerostin) peptide and increases bone density... </li></ul>
  8. 8. Anti-Sclerostin Antibody in Clinical Trials
  9. 9. Example 2: Protective Allele in Crohn’s
  10. 10. IL23 Pathway as a Drug Development Target <ul><li>Loss-of-function alleles lead to reduced disease risk </li></ul><ul><li>Similar genetic effects in psoriasis, rheumatoid arthritis and ankylosing spondalytis </li></ul><ul><li>Several patent applications for IL-23 antibodies and antagonists </li></ul><ul><ul><li>Identified as a target before the mapping data was available </li></ul></ul>
  11. 11. IL-23 Antagonist in Clinical Trials This work pre-dated the genetic mapping results
  12. 12. “ Drug Surrogate” Mutations <ul><li>Discovery of the sclerosteosis mutations directly led to the development of a drug for osteoporosis </li></ul><ul><li>Drug surrogate mutations </li></ul><ul><ul><li>Modulate disease characteristics </li></ul></ul><ul><ul><li>Loss-of-function = small molecule or antibody </li></ul></ul><ul><ul><li>Gain-of-function = therapeutic protein </li></ul></ul><ul><li>Human genetics yields superior targets </li></ul><ul><ul><li>Human proof-of-principle before clinical trials are started </li></ul></ul><ul><ul><li>Superior to animal models </li></ul></ul><ul><ul><li>Clinical trials are easier to justify if you know the answer before you start </li></ul></ul>
  13. 13. Mapping Strategy <ul><li>Use clinical data and genealogy information to identify individuals and pedigrees </li></ul><ul><li>Sequence to identify mutations </li></ul><ul><ul><li>Recent proof of principle at ISB and other groups </li></ul></ul><ul><li>Develop new genetic and statistical tools to maximize the value of the data </li></ul><ul><ul><li>Tools to combine data from multiple rare, uncharacterized mutations </li></ul></ul>
  14. 14. Examples <ul><li>Low or high lipid levels without disease </li></ul><ul><li>Fat taste sensitivity and BMI </li></ul><ul><li>Type II diabetes without sequelae </li></ul><ul><ul><li>Retinopathy, neuropathy, nephropathy and arteriosclerosis </li></ul></ul><ul><li>Cell-based immunological screens </li></ul><ul><li>Obesity without Type II Diabetes </li></ul><ul><li>Non-pathological physiological abnormalities </li></ul>
  15. 15. Changing the Economics of Drug Development <ul><li>The biggest cost of drug development is the cost of failure </li></ul><ul><ul><li>Development costs for 90% of targets that fail in clinical trials amortized over the few successful drugs </li></ul></ul><ul><li>Use human genetic variation to identify and validate targets that will not fail in clinical trials </li></ul><ul><ul><li>All of the significant medical and scientific risks with AMG 785 (the SOST antibody) were answered in Phase I </li></ul></ul><ul><ul><li>With current technology, we could go from a family pedigree like sclerosteosis to an antibody ready for Phase I trials for a few million dollars </li></ul></ul><ul><li>This approach requires access to collaborators with linked medical and genealogical records </li></ul>
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