Retinal Diseases & Glaucoma - New Therapeutic Strategies

Venue: Double Tree Grand Hotel

Location: Miami, Florida,

Event Date/Time: Mar 21, 2002 End Date/Time: Mar 22, 2002
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9:05 Myocilin Glaucoma Genetics
John H. Fingert, M.D., Ph.D., Department of Ophthalmology and Visual Sciences, University of Iowa Hospitals and Clinics
Mutations in the myocilin gene have been associated with juvenile-onset open angle glaucoma and primary open angle glaucoma. The role of variations in this gene and its promoter have also been explored in other forms of glaucoma and in responsiveness to drug therapy. New data in this area will be discussed.
9:40 The Glaucoma Gene MYOC: New Discoveries and a Potential New Therapeutic Target
Abbot F. Clark, Ph.D., Sr. Director, Therapeutic Target Discovery, Alcon Research, Ltd.
(MYOC) Myocilin was the first glaucoma gene mapped and identified. MYOC is expressed in the trabecular meshwork TM and optic nerve head, two tissues involved in the pathogenesis of glaucoma. This gene encodes a secreted glycoprotein and is induced indirectly by glucocorticoids in TM cells. Glaucomatous mutations in MYOC inhibit myocilin secretion from TM cells and are associated with ultrastructural changes in the TM secretory pathway. It has been suggested that MYOC is involved in glucocorticoid-induced ocular hypertension. We have recently discovered a new agent, anecortave acetate, which suppresses the glucocorticoid induction of MYOC in cultured TM cells. This agent also lowers IOP in steroid-induced ocular hypertensive rabbits and man.

10:15 Central Modulation of Intraocular Pressure
Miller J. Ogidigben, Ph.D., Dept. of Pharmacology, Merck & Co., Inc., Merck Research Laboratories
Increased intraocular pressure (IOP) remains the only modifiable risk fact in open angle glaucoma. It is broadly reported in the literature that unilateral topical instillation of selected ocular hypotensive agents elicit contralateral reduction of IOP in laboratory animals and humans. I hypothesize therefore that ocular hypotensive compounds act at intra and extraocular sites (brain) to effect ocular hydrodynamics.

10:50 Refreshment Break and Exhibit / Poster Viewing

11:15 The Molecular Pathway of Ganglion Cell Death in Glaucoma
Robert W. Nickells, Ph.D., Associate Professor, Department of Ophthalmology and Visual Sciences, University of Wisconsin
The primary outcome of glaucoma is the death of retinal ganglion cells by a mechanism that has characteristics of apoptosis. Genetic studies in mice have been used to elucidate the series of molecular events that are initiated from the time of activation of the cell death program to the complete degradation of the cell. Points at which this pathway may be interrupted will be discussed.

11:50 TNF-a in Glaucomatous Neurodegeneration
Gulgun Tezel, M.D., Assistant Professor, Department of Ophthalmology & Visual Sciences, Washington University School of Medicine
This talk will present current evidence suggesting that TNF- a is a potentially important mediator of retinal ganglion cell death in glaucoma. In vitro and in vivo evidence demonstrates that TNF- a mediated cell death can be triggered in retinal ganglion cells by stressors commonly thought to be causative in glaucoma such as elevated intraocular pressure and ischemia. In addition, glial production of TNF- a is increased, and TNF receptor-1, a death receptor, is upregulated in retinal ganglion cells in human donor eyes with glaucoma. Better understanding the precise mechanisms of glaucomatous neurodegeneration can facilitate development of effective strategies for neuroprotection.

12:25 Luncheon, Sponsored by The Knowledge Foundation, Inc.

1:55 Chairperson's Opening Remarks
Larry Wheeler, Ph.D., Allergan, Inc.

2:00 Apoptosis Signaling in Glaucoma: An Opportunity For Therapy
William G. Tatton, M.D., Ph.D., Departments Of Ophthalmology And Neurology, Mount Sinai School Of Medicine
Blindness caused by glaucoma largely results from a progressive loss of retinal ganglion cells (RGCs). Although the factors that initiate glaucoma are not fully understood, recent research has established that glaucomatous RGC loss involves the process of apoptosis. Apoptosis is a relatively gradual process that depends on signaling pathways, which principally involve protein-protein interactions. The pathways vary for different physiological and pathological processes. Accordingly, an understanding of apoptosis signaling in glaucoma holds the promise of selectively interrupting RGC loss in the disease. We have investigated apoptosis signaling in an animal glaucoma model and postmortem glaucomatous eyes. A signaling pathway involving the proteins p53, glyceraldehyde-3-phosphate, BAX, BCL-2/BCL-XL and activated caspase 3 has been identified. Two families of pharmacological agents, propargylamines and a2-adrenergic receptor agonists have been found to interrupt the pathway and to reduce glaucomatous RGC apoptosis in animals.

2:35 Role of Alpha-2 Adrenergic Receptors in Neuroprotection and Glaucoma

Purpose: Evaluate neuroprotection by the alpha-2 adrenergic agonist brimonidine. Methods: Brimonidine effects assessed in optic nerve crush and ocular hypertensive rat models and in growth factor-deprived PC-12 cells. Results: Rats with induced >2-fold elevation of IOP show 35% loss of retinal ganglion cells after 3 weeks; the loss was 12% in rats treated constantly with brimonidine. Brimonidine pretreatment reduced neuronal loss after optic nerve crush. Brimonidine maintained Bcl-2 levels, prevented mitochondrial permeability transition, and enhanced the survival of growth factor-deprived differentiated PC-12 cells by 55%-83%. Conclusions: Brimonidine activates survival pathway(s) and raises the resistance of neurons to stress and injury.

3:10 Refreshment Break and Exhibit / Poster Viewing


3:45 Characterization of Pathways and Genes Involved in the Etiology of Age-Related Macular Degeneration
Gregory S. Hageman, The University of Iowa Center for Macular Degeneration, Department of Ophthalmology and Visual Sciences
Age-related macular degeneration (AMD) is a blinding disease that currently afflicts millions of adults in the United States and an even greater number in the rest of the Western world. The sequelae of biochemical, cellular, and/or molecular events leading to the development of AMD have been poorly understood, although recent studies have provided compelling evidence that inflammation and other immune-mediated processes play an integral role in the etiology of AMD. These data will be reviewed.
4:20 The Development of Genetically Modified RPE Cell Lines and their Evaluation in Transplantation Strategies for the Treatment of Retinal Degeneration
John Greenwood, Professor, Ph.D., FRCPath, Endothelial and Epithelial Cell Biology Research Unit, Division of Cell Biology, Institute of Ophthalmology, University College London
In this presentation we will describe the development and characterization of human retinal pigment epithelial (RPE) cell lines with particular emphasis on those properties thought to be important to cell survival and function. Using the RCS rat, in which there is retinal degeneration contingent on RPE cell dysfunction, we will show that subretinal grafting of these cell lines preserves visual function as assessed both physiologically and behaviorally. These studies demonstrate the potential for such cell lines in the treatment of patients with age-related macular degeneration.

4:55 End of Day One

Friday, March 22, 2002
8:15 Coffee, Pastries and Exhibit/Poster Viewing

9:00 Chairperson's Remarks
William W. Hauswirth, Department of Molecular Genetics and Microbiology, Center for Gene Therapy, University of Florida

Retinal Edema

9:05 Nepafenac Inhibits Concanavalin-A Mediated Pan Retinal Edema
Michael A.Kapin, Director, Retinal/Degenerative Research, Alcon Research Ltd.
Inflammation has long been associated with the pathophysiology of retinal edema. In these studies, anti-inflammatory efficacy of nepafenac, a unique nonsteroidal anti-inflammatory prodrug, was assessed following topical administration in rabbits. Nepafenac dose-dependently inhibited mitogen-mediated increases in retinal thickness, blood-retinal barrier breakdown and prostaglandin synthesis. When compared against Voltaren or Acular, nepafenac exhibited superior biodistribution and efficacy in the posterior segment, suggesting a unique therapeutic potential in treating retinal edema. *In collaboration with D.A.Gamache, G. Graff, J.M. Yanni, Alcon Research Ltd., J.G. Flanagan, U. Toronto, Canada.
9:40 Eyeing P2Y Receptor Agonists for Retinal Detachment and Edema
Ward M. Peterson, Ph.D., Director, Preclinical Programs, Inspire Pharmaceuticals
Pathological accumulation of fluid within the subretinal space (retinal detachment) or retina (retinal edema) results in visual loss in many ocular diseases. The P2Y2 receptor in the retinal pigment epithelium is a potential therapeutic target to stimulate the removal of extraneous fluid in the subretinal space and retina. INS37217 is a hydrolysis-resistant P2Y 2 receptor agonist and was shown in preclinical studies to significantly enhance the reabsorption of subretinal fluid in rat, rabbit, and pig models of retinal detachment. INS37217 is currently in clinical development for the treatment of retinal detachment and edema.

10:15 Refreshment Break and Exhibit / Poster Viewing

Angiogenesis and Neovascularization

10:45 Gene Delivery for the Treatment of Ocular Diseases
Lisa L. Wei, Ph.D., GenVec, Inc.
Ocular gene therapy offers many advantages over gene therapy directed to other tissues in that (1) the eye is easy accessible, making delivery of a therapeutic gene relatively easy, (2) gross morphological changes that may occur in tissue structure after gene delivery are easily observable with an ophthalmoscope, and (3) the built-in barriers of the ocular space provide an enclosed system that may prevent diffusion away from the site of injection and may also offer a degree of immune privilege. Our working hypothesis is that adenovirus vectors are a useful gene delivery system for the treatment of ocular diseases (i.e., wet age-related macular degeneration and diabetic retinopathy). Combining this with a powerful antiangiogeneic gene such as Pigment Epithelium-Derived Factor (PEDF) could provide a potential breakthrough product for ocular neovascular diseases. We tested an adenovector containing PEDF (AdPEDF) in three experimental models of neovascularization in mice. These proof-of-principle experiments demonstrate that PEDF can inhibit both choroidal and retinal neovascularization by a gene delivery method.
11:20 VEGF In Ocular Angiogenesis: Normal and Pathological Angiogenesis in the Eye
Michael R. Niesman Ph.D., Director, Ophthalmology Drug Discovery, Pfizer Global Research and Development, La Jolla Laboratories
Vascular endothelial growth factor (VEGF) supports the growth and development of the retinal vasculature. Additionally, it appears to drives the inappropriate growth of blood vessels in the cornea, iris, trabecular meshwork, and retina. Pathological angiogenesis, or neovascularization, is a leading cause of blindness in developed countries. VEGF has been implicated as a key player in ocular neovascularization. Various strategies for inhibiting VEGF within the eye will be reviewed with an emphasis on understanding the advantages and drawbacks of these inhibitors and how they may prevent neovascularization and improve the outlook for patients at risk for blindness.

11:55 Ocular Application of Antisense Therapeutics: Effect of Blocking MAP Kinase Signaling on Retinal Angiogenesis
Scott P. Henry, Ph.D., DABT, Director of Toxicology,
Isis Pharmaceuticals, Inc.
With the increased knowledge of the molecular mechanisms of ocular diseases, the potential impact of gene-specific therapeutics increases. Antisense therapeutics have great potential in cases where inhibition of expression of a particular gene is desired. Experience gained in the treatment of CMV retinitis by this method illustrates the potential opportunities. Local application results in the efficient exposure of ocular target tissues and cell types to the agent, while avoiding systemic exposure. This talk will focus on recent progress in the areas of improved potency, pharmacokinetics, and tolerability of second-generation antisense oligonucleotides. Examples will be presented in the context of current research into the treatment of retinal angiogenesis.

12:30 Lunch on Your Own

1:55 Chairperson's Remarks
Ward M. Peterson, Ph.D., Director, Preclinical Programs, Inspire Pharmaceuticals

2:00 Pharmacodynamic Evaluation of Anti-Angiogenic Agents in Experimental Models of Ocular Neovascularization
Jeffrey L. Edelman, Ph.D., Senior Scientist, Drug Discovery, Allergan, Inc.
The extravasation and edema that results from aberrant new vessel growth within normally transparent ocular tissues causes severe vision loss in several ocular diseases including diabetic retinopathy and age-related macular degeneration. Although there are no animal models which reliably mimic these retinal diseases, experimental models of corneal, iris, retinal, and choroidal neovascularization are being used to evaluate the efficacy and safety of several anti-angiogenic strategies (e.g. photosensitizers, angiostatic steroids, COX inhibitors, tyrosine kinase inhibitors). Our experience with some of these anti-angiogenic agents in ocular neovascularization models will be discussed.

2:35 AAV-Vectored Gene Therapy for Choroidal and Retinal Neovascularization in Animals
William W. Hauswirth, Department of Molecular Genetics and Microbiology, Center for Gene Therapy, University of Florida
The severe vision loss associated with AMD or diabetic retinopathy is caused in large part by the invasive growth of blood vessels into the retina proper. Two potent inhibitors of neovascularization are PEDF and angiostatin. When delivered intraocularly as genes in AAV, each effectively limits such pathogenic vascularization in two rodent models, laser-induced choroidal neovascularization and ischemia-induced neonatal retinal neovascularization.

3:10 Refreshment Break and Exhibit / Poster Viewing

Gene Therapy

3:40 Gene Therapy to Treat Childhood Retinoblastoma Using an Adenoviral Delivery System: Safety, Toxicity and Potential Efficacy
Richard L. Hurwitz, M.D., Associate Professor Pediatrics, Ophthalmology, and Molecular and Cellular Biology, Director, Retinoblastoma Center, Texas Children's Cancer Center, Center for Cell and Gene Therapy, Baylor College of Medicine
Dr. Hurwitz studies the use of gene therapy in the treatment of ocular disease. Retinoblastoma is the most common malignant intraocular tumor of children and a disease known to be caused by mutations in the retinoblastoma gene. Using a mouse model of this disease, suicide gene therapy using an adenoviral vector to deliver the herpes thymidine kinase gene followed by ganciclovir was shown to shrink the tumor. Based on these studies, a FDA- and RAC-approved clinical trial to investigate the use of this therapy for children with retinoblastoma has been opened. We will talk about the safety, toxicity, and potential efficacy of using an adenoviral delivery system for ocular disorders.
4:15 Toxicity and Pharmacokinetics of Proliferating Cell Nuclear Antigen Ribozyme Against Cell Proliferation in Proliferative Vitreoretinopathy (PVR)
Joan M. Robbins, Ph.D., Senior Director, Product Development, Immusol, Inc.
Abstract not available at time of print.

4:50 End of Conference