Transcript The National Eye Institute Supercourse

The National Eye Institute
Supercourse
Paul A. Sieving, MD, PhD
Director
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 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.
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 we
understand the root causes or “biological mechanisms”
that cause disease. With this knowledge, we can develop
therapies 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 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).
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!
Proteomics
Bioinformatics 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.
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
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.
Translational Research at the
Movies
Dogs with condition similar to LCA
Human Clinical Trail Planned for 2007
Two Big Thumbs Way Up!!!
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.
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.
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.
CNTF delivered via ECT Device Rescues
photoreceptors in rcd1 dog RP model
ECT Implanted at 7 wks.
CNTF-ECT
treated
Non-treated
fellow eye
Explanted at 14 wks.
Rescue of rods in
CNTF treated eye.
Loss of rods
in untreated eye
Aguirre & Tao, 2002.
Cross Section of ECT device
Immune System
Molecules
Semipermeable Membrane
Oxygen & Nutrients
15 nm
pore size
Therapeutic Molecules
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.
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
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Acuity Change in Fellow Eye
Change from Baseline
Change from Baseline
Acuity Change in Study Eye
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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.
CNTF Implanted Eye - Higher Output Device
Control Fellow Eye - Higher Output Device
Visual Acuity Change
Visual Acuity Change
VA Change from Baseline
VA Change from Baseline
• 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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Ophthalmology has come a long way
since I started practicing…
Offices of
Dr. Paul Sieving M.D., Ph.D.
Sieving
…but it still has a long way to go!
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