Forward-looking Research: The Potential of New Genetic Technologies


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Dr. James Gusella discusses the research cycle of Norrie Disease. (NDA International Conference, 2009)

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Forward-looking Research: The Potential of New Genetic Technologies

  1. 1. James F. Gusella, PhD Center for Human Genetic Research - Massachusetts General Hospital Forward-looking Research: The Potential of New Genetic Technologies
  2. 2. Effective ND Therapies This is the ultimate mission of Norrie Disease investigators/clinicians <ul><li>Pharmaceutical: traditional small molecule drugs </li></ul><ul><li>Biological: proteins, gene manipulation </li></ul><ul><li>Medical device </li></ul>Potential types of therapeutic intervention
  3. 3. Molecular Target Screen chemical compounds Optimize selected compounds Preclinical testing- model systems Phase 1 Clinical Trial Phase 2 Clinical Trial Phase 3 Clinical Trial FDA approved drug Traditional Pharmaceutical Development Basic Research Applied Research Clinical Trial Research Flexibility, variety of strategies
  4. 4. Therapeutic development It requires 3 different kinds of research: Basic/Discovery research Applied/translational research Clinical trial research
  5. 5. Why not just guess at a drug?
  6. 6. Why not just guess at a target or test all of them?
  7. 7. Norrie Patients and Families Identification of Norrie disease gene How do norrin mutations cause disease symptoms? Diagnostics, Management and Therapy Norrie Disease Genetic Research Cycle Description of disorder
  8. 8. Norrin protein
  9. 9. Norrin
  10. 11. How do mutations cause disease symptoms Why? To identify a specific molecular target or pathway against which an effective drug can be developed How? Basic Research
  11. 16. How to define the effects of the Norrie disease mutation? <ul><li>Advances in high throughput biology – permits unbiased mining of large datasets and definition of global pathway changes </li></ul><ul><li>Advances in DNA sequencing are opening up the search for factors that modify disease </li></ul><ul><li>Advances in stem cell technology will permit the study of norrin function in authentic human cells of different types </li></ul>
  12. 18. Genetic models with inbred mice are identical clones of each other 50 72 80 92 111 150
  13. 20. Manual DNA sequencing: from the era of Norrie gene discovery Only a few hundred thousand bases per person per year
  14. 21. Semi-automated DNA sequencing: Led to sequencing of the entire human genome for ~3 billion dollars
  15. 22. Automated “next-generation DNA sequencing: Currently can provide full genome sequence for $5,000-$20,000 Expected to drop to less than $1,000 with 1-2 years Realistic to sequence whole genomes and for other applications to more rapidly identify factors that modify disease – identify targets and pathways for therapeutic intervention that are already validated in humans or human cells
  16. 23. Despite appearances, mice are not people
  17. 24. Stem cells and iPS cell
  18. 25. Pluripotent stem cells can be made from adult skin cells
  19. 27. Advances in applied research <ul><li>Pharmaceutical companies are beginning to investigate a pathway-based therapeutic approach </li></ul><ul><li>Human cell models may be more predictive of potential therapeutic benefit than non-human models </li></ul><ul><li>Research advances in the ability to manipulate gene expression: RNA interference, microRNAs, sequence specific targeting </li></ul><ul><li>Research advances in experimental delivery systems for gene-based biologicals </li></ul>
  20. 28. <ul><li>Research requires the cooperation and participation of patients at all stages for: </li></ul><ul><li>detailed description of disease in all its aspects </li></ul><ul><li>biological samples for discovery and applied research </li></ul><ul><li>clinical research into effectiveness of candidate interventions </li></ul>Empowering the Research Pipeline
  21. 30. Thank you