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

1. James F. Gusella, PhD Center for Human Genetic Research - Massachusetts General Hospital Forward-looking Research: The Potential of New Genetic Technologies

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. Therapeutic development It requires 3 different kinds of research: Basic/Discovery research Applied/translational research Clinical trial research

5. Why not just guess at a drug?

6. Why not just guess at a target or test all of them?

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. Norrin protein

9. Norrin

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

18. Genetic models with inbred mice are identical clones of each other 50 72 80 92 111 150

20. Manual DNA sequencing: from the era of Norrie gene discovery Only a few hundred thousand bases per person per year

21. Semi-automated DNA sequencing: Led to sequencing of the entire human genome for ~3 billion dollars

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

23. Despite appearances, mice are not people

24. Stem cells and iPS cell

25. Pluripotent stem cells can be made from adult skin cells

30. Thank you