Therapeutic Developments for RETINAL DISEASES AND GLAUCOMAMarch 15 - 16, 2001 • Hyatt Regency • San Francisco, CA USA [ Overview | Agenda | Call for Posters | Register ] View Electronic Brochure (PDF)OverviewThis international conference focuses on the advantages and limitations of new techniques in developing treatments for glaucoma and retinal diseases. New opportunities for therapeutic approaches are of paramount importance to this emerging field. Recent advances in the use of genomics to identify glaucoma associated genes and a novel hypothesis of ganglion cell death in glaucoma will be covered. Gene delivery by herpes simplex virus vectors for treatment of ocular disease will be discussed in a model of retinal degeneration as well as the advantages and problems of photodynamic therapy for treatment of age related macular degeneration. Program Features will include: Furthermore, you will learn about the first development of an artificial retina and new mechanisms to repair the outflow system of the eye. Don't miss the opportunity to discuss new approaches and innovative strategies for treatment of retinal disease and glaucoma with the top experts. Early registration ensures your participation. Reserve your seat today! RELATED LINKSExperimental Eye Research Ocular Surgery News AgendaThursday, March 15, 20018:00 Registration, Poster/Exhibit Set-Up, Coffee and Danish GLAUCOMA9:00 Chairperson's Opening Remarks Gene Discovery and Delivery9:05 Using Genomics to Discover Glaucoma Associated Genes Although the glaucomas are a prevalent cause of visual impairment and blindness in the world, there is very little known about the molecular pathogenesis of this heterogeneous group of diseases. The rapid advances being made in genomics are being applied to better understand the pathobiology of glaucoma and to devise better therapeutic approaches. RNA differential display, cDNA subtraction cloning, and DNA microarrays are being used to identify differentially expressed genes in normal and glaucomatous cells and tissues from the trabecular meshwork, optic nerve head, and retina. The follow-up of differential gene ÒhitsÓ is a major challenge that requires independent verification of differential gene expression, expression profiling in ocular and nonocular tissues, chromosome mapping, and functional studies. 9:40 Herpes Simplex Virus Vectors for Ocular Gene Delivery: Promise and Problems The use of gene delivery to treat ocular disease is particularly attractive due to accessibility and compartmentalization of the tissues. HSV based vectors have several potential advantages including ability to transduce many cell types, large carrying capacity, and lack of genomic integration. This talk will discuss the use of HSV vectors for ocular gene delivery including cell types transduced, side effects, efficiency of delivery and pathogenesis in rodent and primate models. Finally, the use of HSV vectors for delivery of a neuroprotective gene in rodent models of retinal degeneration will be considered. Intraocular Pressure and Outflow System10:15 A Novel Hypothesis of Ganglion Cell Death in Glaucoma Traditionally, ganglion cell (GC) loss in glaucoma is thought to result from intraocular pressure (IOP)-mediated damage to the axons of the GCs as they pass through the optic nerve head. The GC bodies then die by retrograde degeneration, following loss of their downstream connections. Evidence will be presented supporting another possible mechanism of GC death in glaucoma. Namely, that elevated IOP reduces choroidal blood flow resulting in photoreceptor injury. The injured photoreceptors, in turn, may release excess (or fail to re-uptake) glutamate, their primary excitatory neurotransmitter, which overexcites the downstream cells. In other words, the pathologic insult progresses in an anterograde direction from the outer retina to the GCs. 10:40 Refreshment Break and Poster/Exhibit Viewing 11:20 Regulation of myocilin/TIGR gene expression Increased amounts of myocilin/TIGR have been observed in the trabecular meshwork (TM) of eyes with primary open-angle glaucoma. Factors that induce the expression of myocilin/TIGR in TM cells are dexamethasone, transforming growth factor-beta and mechanical stretch. Upstream stimulatory factor has been identified as a key element that regulates myocilin/TIGR expression at the level of transcription. So far it is unclear, if the increased expression of myocilin/TIGR in glaucoma contributes to the increase in intraocular pressure, or rather is a reaction of the TM in response to an increase in mechanical strain. 11:55 Studies of TIGR gene biosynthesis: regulation by hormones/modulators and characterization of translocational 'pausing' The regulation of mRNA and protein expression of TIGR by a variety of "stress" factors, including hormones and modulators, could be related to altered physiological outflow in glaucoma whether or not the gene has coding region defects. Alterations in targeting, including direct effects of specific mutations and those we have attributed to alterations in translocational pausing of TIGR could help to explain potentially important pathways for the biogenesis of this complex secretory protein Ñ and thus contribute to disease pathogenesis. In our laboratory, we have characterized the TIGR protein for functional domains involved in translocational pausing that may be relevant to both the physiological role(s) of the protein and pathological alterations due to mutations in the geneÕs coding region. 12:30 Lessons From a Rat Model of Glaucoma Understanding the mechanisms of glaucomatous optic nerve damage requires the development of a suitable animal model that closely mimics the clinical disease. By creating selective scarring of aqueous humor outflow channels in laboratory rats, it is possible to increase intraocular pressure, a major risk factor for glaucoma. Our experience with this model shows that the resulting pressure rise exhibits greater than normal fluctuations, and that this pressure rise is markedly diminished by general anesthetics. Since these effects are also seen in human glaucoma, this underscores the importance of a diminished aqueous outflow in this disease. The cost-effectiveness of this model also allows studies of message and protein responses to chronically elevated pressure. This has lead to new insights into the role of altered neurofilament production, phoshphorylation and transport as mechanisms of glaucomatous optic nerve injury. 1:05 Luncheon Hosted by The Knowledge Foundation RETINAL DISEASES2:30 Second Sight-A Company Developing A Retinal Prosthesis For Patients Blinded By Outer Retinal Degenerations In 1755 LeRoy discovered that an electric charge delivered to the blind eye produced a sensation of light. Ever since, man has pondered the possibility of making the blind see. However, it wasn't until the age of modern electronics that building such a device became possible. In the 1960's, Dr. Brindley in England elicited sensations of light in blind subjects by electrically stimulating their visual cortex (the back side of their brain). In the 1970's, Dr. Dobelle in the U.S. repeated these experiments with some success. However, the resolution achieved by these early devices was very poor. At best, these patients could read Braille by the flashing lights (phosphenes). By the time the visual image has reached the brain, a significant amount of processing has already occurred - making fine resolution difficult to achieve. Another problem with this approach was that the surgery was very invasive and dangerous for these volunteer patients. Over the past decade at Johns Hopkins, we discovered that there is a subpopulation of blindness (outer retinal degenerations such as Retinitis Pigmentosa) in which a majority of the retina and visual system is intact, allowing stimulation more peripherally - at the retina. 3:05 Photodynamic Therapy of Age-Related Macular Degeneration, Its Pitfalls and Problems This presentation deals with background and rationale of photodynamic therapy in the treatment of age-related macular degeneration. Experimental findings are presented to minimize the complications of this procedure. 3:40 Refreshment Break and Poster/Exhibit Viewing Enzymatic Approaches4:15 Aldose-Reductase Linked Pericyte Degeneration is Linked to Retinal Vessel Changes Associated with Diabetic Retinopathy in Galactose-Fed Dogs Galactose-fed beagles develop diabetes-like microvascular changes associated with all stages of diabetic retinopathy. These changes begin with the selective degeneration of retinal capillary pericytes and this degeneration can be ameliorated through the inhibition of aldose reductase catalyzed production of galactitol. Tissue culture studies indicate that pericyte degeneration results from apoptosis which is initiated by the intracellular accumulation of galactitol. 4:50 The Use of the Enzyme Hyaluronidase (Vitrase) in the Treatment of Retinal Diseases Abstract not available at time of print 5:30 End of Day One Friday, March 16, 20018:45 Exhibit/Poster Viewing, Coffee and Danish Ocular Angiogenesis9:25 Chairperson's Opening Remarks 9:30 Anecortave Acetate: a New Ocular Angiostatic Agent There are a number of blinding ophthalmic neovascular diseases for which there are no satisfactory drug therapies. Anecortave acetate (AL-3789) is a new angiostatic steroid that inhibits angiogenesis in eight different preclinical models of neovascularization. Anecortave acetate is devoid of conventional pharmacological activities and does not have the ocular liability of a glucocorticoid. Preclinical toxicology and human clinical studies show that anecortave acetate is a safe angiostatic agent. Recent clinical studies have shown that topical ocular anecortave acetate significantly inhibits the regrowth of ocular fibrovascular membranes in patients with recurrent pterygium, and phase I/II clinical trials are underway in AMD patients with subretinal neovascular membranes. 10:05 Ocular Angiogenesis: The Key Role of Vascular endothelial growth factor (VEGF) is an important factor in the development of the retinal vasculature, However, it also drives the inappropriate growth of blood vessels in the cornea, iris, trabecular meshwork, and retina. This pathological angiogenesis, or neovascularization, is a leading cause of blindness in developed countries. Although many factors contribute to inappropriate blood vessel growth, vascular endothelial growth factor (VEGF) is involved in the early stages of neovascularization. Our increasing understanding of the process of neovascularization in ocular tissues has spurred research into several strategies for inhibiting the action of this protein. The strategies for inhibiting VEGF within the eye will be reviewed with an emphasis on understanding how these inhibitors may prevent neovascularization and improve the outlook for patients at risk for blindness. 10:40 Vascular Targeting Agents - New Method to Target Ocular Neovasculature caused by Angiogenesis Presently, photocoagulation has been used to stem the progression of ocular neovasculature. Although such treatment has the ability to slow down vascularization, it cannot completely remove existing vasculature. Additionally, anti-angiogenic agents may be another means to stem the progression of aberrant neovasculature. These agents work by inhibiting the progression of aberrant neovasculature without the ocular toxicity of photocoagulation. However, anti-angiogenic agents as in photocoagulation are unable to completely remove existing vasculature. Hence, neither of these treatments are able to completely restore visual acuity lost by the presence of aberrant neovasculature. OXiGENE's combretastatin A4 Prodrug (CA4P) is the first in a class of molecules able to attack existing neovasculature, not just inhibiting the formation of such vasculature. Work will be described here to show how CA4P is thought to function as a vascular targeting agent both on a mechanistic level and in application to ocular neovascularization. 11:15 Refreshment Break and Poster/Exhibit Viewing Drug delivery and distribution11:45 The Microdialysis Approach to the Evaluation of Anterior Segment Disposition and Pharmacodynamics of Topically Administered Drugs in the Conscious Animal This talk will outline the development of a conscious animal model using microdialysis for the examination of the ocular pharmacokinetics and pharmacodynamics of drugs that modulate aqueous humor formation. A model substrate, a beta-adrenergic antagonist, is examined for it's effects on the rate of aqueous humor formation as well as effects on an endogenous surrogate marker, ascorbate. Strengths and limitations to microdialysis approach are discussed in the context of the observed experimental results. Data analysis and interpretation tools including classical pharmacokinetic modeling and non-compartmental analysis will be discussed. 12:20 Permeability and Diffusion in Vitreous Humor - Implications for Drug Delivery Previous experimental work suggests that convection may be important in determining the biodistribution of drugs implanted or injected in the vitreous humor. To develop accurate biodistribution models, the relative importance of diffusion and convection in intravitreal transport must be assessed. This requires knowledge of both the diffusivity of candidate drugs and the hydraulic conductivity of the vitreous humor. We measured hydraulic conductivity of cadaveric bovine vitreous humor by confined compression tests, and analyzed the results numerically using a two-phase model. Hydrualic conductivities, combined with experimentally measured diffusivities, allow us to predict that convection does not contribute significantly to transport in the mouse eye, particularly for low-molecular-weight compounds. For delivery to larger animals, such as humans we conclude that convection accounts for roughly 30% of the total intravitreal drug transport. This effect should be magnified for higher-molecular-weight compounds, which diffuse more slowly, and in glaucoma, which involves higher intraocular pressure and thus potentially faster convective flow. Thus, caution should be exercised in the extrapolation of small-animal-model biodistribution data to human scale. A three-dimensional finite-element model of diffusive and convection transport in the eye also will be presented. This model shows the importance of injection location, convection, and diffusion on biodistribution of drugs administered to the vitreous humor. 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