The National Eye Institute Supercourse

1. The National Eye Institute Supercourse Paul A. Sieving, MD, PhD Director Department of Health and Human Services

2. The Human Eye

3. Eye Diseases Age-related macular degeneration (AMD) is the leading cause of vision loss and legal blindness in older Americans. Over 1.8 million Americans have severe vision loss from AMD; 7 million are at risk. Glaucoma affects over 2 million Americans. African Americans are disproportionately affected with a rate three times that of Caucasians. 20.5 million Americans over age 65 have either developed cataracts or currently suffer from the condition. Images courtesy Uni. of Michigan

4. Eye Diseases Diabetic retinopathy, a complication of diabetes, affects 4.1 million Americans. One in 12 people with diabetes over age 40 has lost vision to diabetic retinopathy. Uveitis, an inflammatory disease within the eye, accounts for 10 percent of blindness in the U.S. Retinopathy of prematurity affects thousands of low-weight, premature infants each year. An estimated 3 percent of children in the United States suffer visual impairment from amblyopia.

5. Public Health Challenge of Vision and Eye Care • 38 million in the U.S. suffer vision limitation from diseases and conditions that in majority have a genetic basis • Americans age >40 years with age-related eye disease will increase 40% by 2020. • Eye diseases and disorders cost $60 billion annually in the U.S. Clearly, there is a critical need for new and more effective therapies.

6. The development of new treatments requires that we understand the root causes or “biological mechanisms” that cause disease. With this knowledge, we can develop therapies that overcome disease.

7. How Do We Develop New Treatments? Genetics Proteomics Translational Research Clinical Trials

8. Genetics • Within the nucleus of every human cell are approximately 30,000 genes that control life. • Each gene is like a complex computer program containing biologic code that instructs a cell to create a unique protein. • Each unique protein performs a specific function within a cell.

9. Genes to Proteins

10. Genes to Proteins • Sometimes, genes contain “errors” or mutations that interfere with the proper coding of a protein.

11. Mutant Genes in Eye Diseases Cornea: ARSC1, CHST6, COL8A2, GLA, KRT3, and KRT12 lattice corneal dystrophies associated with amyloid deposition (GSN, M1S1, TGFBI [BIGH3]). Lens: Congenital Cerulean CCA1, Crystallins (CRYAA, CRYAB, CRYBA1, CRYBB2...), Aniridia AN2, Forkhead, FOXE3. Retina: Retinitis Pigmentosa (RHO, RPGR, RPE65, RDS, PRPF8); Macular degeneration (ARMD1, EFEMP1, ELOVL4, RDS, TIMP3, VMD2, ABCA4, RDH4, RPGR); Usher Syndrome (MYO7A, PCDH15, USH3A, USH2A); Bardet Biedl Syndrome (BBS1-4, MKKS, TTC8). Glaucoma: (MYOC, OPTN, CYP1B1); Open angle (GLC1D, GLC1F, GLC3B..). Optic Nerve Atrophy: (OPA1, TIMM8A); Ocular Muscle: Kinesin (CFEOM1, CFEOM3).

12. Proteomics • The study of proteins and their functions in health and disease. Normal Protein Mutant Protein

13. Proteomics Involves Many Disciplines Bio-imaging is important to examine protein location and structure within a cell Fluorescence resonance energy transfer, an imaging technique that tracks structural changes in proteins to explore how changes relate to function Fibronectin (shown in green) is highly expressed during corneal wound healing Photo courtesy Uni. of Washington

14. Proteomics Mass spectrometry is a major tool of proteomics. Thanks to the AO staff for helping the NEI intramural program acquire this and other tools!

15. Proteomics Bioinformatics combines massive computing power and algorithms to aide in the imaging and evaluation of protein structure, interaction and function.

16. Proteomics • Once we understand the structure and function of proteins in health and disease, we can evaluate molecular therapies that inactivate or alter the dysfunctional protein and overcome the disease. • The genetics of many eye diseases are known and the vision research field is leveraging proteomics tools.

17. Translational Research • The interpretation of basic laboratory findings into experimental therapies.

18. Translational Opportunities Leber Congenital Amaurosis (LCA) Normal Retina RPE65 LCA Retina LCA – Early and severe form of retinitis pigmentosa. Infants are born with little or no vision. RPE65 gene cloned in humans and in Briard dogs in 1997.

19. Translational Opportunities RPE65 protein is critical in recycling vitamin A through the retina. Vitamin A is essential to vision. Diagram: Debra Thompson, PhD, University of Michigan

20. Translational Opportunities: Gene Transfer Therapy Restores Vision in Briard Dogs Lancelot, the first Briard with LCA treated with gene therapy in 2000. Still sees 6 years later! Gene transfer restores retinal function as measured by ERG, a standard clinical measure.

21. Translational Research at the Movies Dogs with condition similar to LCA Human Clinical Trail Planned for 2007 Two Big Thumbs Way Up!!!

22. Translational Opportunities Neurotrophic Agents for AMD and RP Neurotrophic factors are a family of genetically encoded proteins that help maintain the health of neuronal cells.

23. Translational Opportunities Ciliary Neurotrophic Factor (CNTF) • CNTF has delayed the loss of retinal cells in 13 different animals with RP and related diseases. • However, the CNTF protein is too large to pass through the blood/retina barrier and so drug delivery is a challenge.

24. Novel Drug Delivery Device to Deliver CNTF Encapsulated Cell Technology (ECT) Hollow fiber membrane 15 nm pore size RPE cells transfected to produce CNTF. Cells placed on scaffold inside the device. 1 mm titanium anchor end seal device length = 6 mm (original 11 mm device) ECT Technology by Neurotech, Inc.

25. CNTF delivered via ECT Device Rescues photoreceptors in rcd1 dog RP model ECT Implanted at 7 wks. Explanted at 14 wks. CNTF-ECT treated Rescue of rods in CNTF treated eye. Non-treated fellow eye Loss of rods in untreated eye Aguirre & Tao, 2002.

26. Semipermeable Membrane Immune System Molecules Oxygen & Nutrients Therapeutic Molecules Cross Section of ECT device 15 nm pore size

27. Clinical Trials Phase I Study of CNTF with ECT device for Retinitis Pigmentosa completed • Study Design: 10 subjects: - 5 received lower dose capsule implant. - 5 received higher dose capsule implant. • Capsule was implanted in one eye for 6 months and then removed to test CNTF output and integrity of capsule and cells.

28. Acuity Change in Study Eye Acuity Change in Fellow Eye 30 30 20 20 10 10 0 0 Change from Baseline Change from Baseline -10 -10 -20 -20 -30 -30 0 1 2 4 8 12 16 20 24 28 0 1 2 4 8 12 16 20 24 28 Weeks After Implant Weeks After Implant Day 1 Day 1 Weeks After Implant Weeks After Implant Subject #2 - CNTF lower output implant. Baseline acuity = 0 letters ETDRS. Visual field = only 23o. ERG = reduced to noise level (“extinguished”). Twenty letter recovery by 6 months on CNTF

29. Control Fellow Eye - Higher Output Device Visual Acuity Change CNTF Implanted Eye - Higher Output Device Visual Acuity Change CNTF results with higher output device. Acuity course of five subjects in Phase I trial. • Safety of CNTF molecule and ECT device was indicated in these 10 subjects. • No inflammation and no complications attributed to the CNTF molecule. • No subject was withdrawn for safety considerations. • Subjects overall showed an upward trend in acuity, but the study was not designed or powered to test significance of this possible outcome.

30. Ophthalmology has come a long way since I started practicing… Offices of Dr. Paul Sieving M.D., Ph.D. Sieving

31. …but it still has a long way to go!

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