The National Eye Institute

Supercourse

Paul A. Sieving, MD, PhDDirector

Department of Health and Human Services

The Human Eye

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

Eye DiseasesDiabetic 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.

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.

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

How Do We Develop New Treatments?Genetics

Proteomics

Translational Research

Clinical Trials

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.

Genes to Proteins

Genes to Proteins• Sometimes, genes contain “errors” or mutations that

interfere with the proper coding of a protein.

Mutant Genes in Eye Diseases

Cornea: ARSC1, CHST6, COL8A2, GLA, KRT3, and KRT12lattice 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).

Proteomics

• The study of proteins and their functions in health and disease.

Normal Protein Mutant Protein

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

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!

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

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.

Translational Research

• The interpretation of basic laboratory findings into experimental therapies.

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.

RPE65 protein is critical in recycling vitamin A through

the retina. Vitamin A is essential to vision.

Diagram: Debra Thompson, PhD, University of Michigan

Translational Opportunities

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.

Translational Opportunities:

Gene Transfer Therapy Restores Vision in Briard Dogs

Translational Research at the Movies

Human Clinical Trail Planned for 2007 Dogs with condition similar to LCA

Two Big Thumbs Way Up!!!

Translational Opportunities

Neurotrophic factors are a family of

genetically encoded proteins that help

maintain the health of neuronal cells.

Neurotrophic Agents for AMD and RP

Translational OpportunitiesCiliary 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.

titanium anchor end seal

RPE cells transfected to produce CNTF. Cells placed on scaffold inside the device.

Hollow fiber membrane 15 nm pore size

device length = 6 mm

1 mm

ECT Technology by Neurotech, Inc.

Novel Drug Delivery Device to Deliver CNTF

Encapsulated Cell Technology (ECT)

(original 11 mm device)

CNTF delivered via ECT Device Rescues photoreceptors in rcd1 dog RP model

Aguirre & Tao, 2002.

CNTF-ECT treated

Non-treated fellow eye

ECT Implanted at 7 wks. Explanted at 14 wks.

Rescue of rods in CNTF treated eye.

Loss of rods in untreated eye

Cross Section of ECT device

Therapeutic Molecules

Oxygen & Nutrients

Semipermeable MembraneImmune System Molecules

15 nm pore size

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.

Baseline acuity = 0 letters ETDRS.

Visual field = only 23o.ERG = reduced to noise level (“extinguished”).

Subject #2 - CNTF lower output implant.

Weeks After Implant

Acuity Change in Study Eye

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Twenty letter recovery by 6 months on CNTF

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.

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Control Fellow Eye - Higher Output Device

Visual Acuity Change

Ophthalmology has come a long way since I started practicing…

Sieving

Offices of

Dr. Paul Sieving M.D., Ph.D.

…but it still has a long way to go!

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