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  Therapeutic developments for retinal diseases & glaucoma  
  December 14, 2000

Medical Research (others)

 
     
  The Knowledge Foundation, Inc., Hyatt Regency, San Francisco, CA, USA
March 15 - 16, 2001


Thursday, March 15, 2001
8:00 Registration, Poster/Exhibit Set-Up, Coffee and Danish

GLAUCOMA
9:00 Chairperson's Opening Remarks
Abbot F. Clark, Ph.D., Sr. Director, Therapeutic Targets Research, Alcon Research, Ltd.

Gene Discovery and Delivery
9:05 Using Genomics to Discover Glaucoma Associated Genes
Abbot F. Clark, Ph.D., Sr. Director, Therapeutic Targets Research, Alcon Research, Ltd.

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
Curtis R. Brandt, Ph.D., Retina Research Foundation Alice McPherson Professor, Departments of Ophthalmology and Visual Sciences, And Medical Microbiology and Immunology, University of Wisconsin Medical School

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 System
10:15 A Novel Hypothesis of Ganglion Cell Death in Glaucoma
T. Michael Nork, M.S.; M.D., Associate Professor, Department of Ophthalmology & Visual Sciences, University of Wisconsin Medical School

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
Ernst R. Tamm, M.D., Associate Professor at the Department of Anatomy, Section on Molecular Anatomy and Embryology, University of Erlangen-Nuernberg, Germany

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'
Carin Zimmerman Ph.D., Department of Ophthalmology, University of California San Francisco

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.
Paused domains are believed to represent regions accessible to the cytosol during protein biogenesis that may be important for correct protein folding and modifications, and this process appears relevant to understanding the effects of certain disease associated mutations.

12:30 Repair mechanism in the outflow system
Ian Grierson, Professor of Ophtalmology, Dept. of Medicine, University of Liverpool, UK

Abstract not available

1:05 Luncheon Hosted by The Knowledge Foundation

RETINAL DISEASES
2:30 Second Sight-A Company Developing A Retinal Prosthesis For Patients Blinded By Outer Retinal Degenerations
Dr. Robert Greenberg, President, Second Sight, LLC

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.
By electrically stimulating the retinas of over a dozen of these patients in the operating room, we were able to achieve formed vision. Stimulating the retina has the potential to provide a much higher resolution device than stimulating the visual cortex and there are now half a dozen groups around the world pursuing this line of research. Here in the Los Angeles area, we have formed a company called Second Sight, which has embarked on creating the first artificial retina - a long-term implantable system which will allow the blind to see.

3:05 Photodynamic Therapy of Age-Related Macular Degeneration, Its Pitfalls and Problems
Gholam A. Peyman, M.D., Professor of Ophthalmology, Tulane University Medical Center, New Orleans

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 Approaches
4:15 Aldose-Reductase Linked Pericyte Degeneration is Linked to Retinal Vessel Changes Associated with Diabetic Retinopathy in Galactose-Fed Dogs
Peter F. Kador, Ph.D., Chief, Lab. Ocular Therapeutics, National Eye Institute

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
Lisa R. Grillone, Ph.D., Vice President, Clinical Research and Medical Affairs, ISTA Pharmaceuticals

Abstract not available

5:30 End of Day One


Friday, March 16, 2001
8:45 Exhibit/Poster Viewing, Coffee and Danish


Ocular Angiogenesis
9:25 Chairperson's Opening Remarks
David Sherris, Ph.D., Vice President of Research and Development, OXiGENE, Inc.

9:30 Anecortave Acetate: a New Ocular Angiostatic Agent
Abbot F. Clark, Ph.D., Sr. Director, Therapeutic Targets Research, Alcon Research, Ltd.

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
VEGF in Normal and Pathological Angiogenesis in the Eye
Michael R. Niesman Ph.D., Pfizer Global Research and Development, La Jolla

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
David Sherris, Ph.D., Vice President of Research and Development, OXiGENE, Inc.

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 distribution
11:45 The Microdialysis Approach to the Evaluation of Anterior Segment Disposition and Pharmacodynamics of Topically Administered Drugs in the Conscious Animal
Kay D. Rittenhouse, Ph.D., Manager, Preclinical Sciences, Bausch & Lomb Pharmaceuticals

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
Theodore W. Randolph, Professor, Dept. of Chemical Engineering, University of Colorado

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.

1:00 End of Conference
 
 
Organized by: The Knowledge Foundation, Inc.
Invited Speakers: Abbot F. Clark, Alcon Research, Ltd.
Curtis R. Brandt, University of Wisconsin
Robert Greenberg, Second Sight, LLC
Lisa R. Grillone, ISTA Pharmaceuticals
Peter F. Kador, National Eye Institute
Michael R. Niesman, Pfizer Gobal R&D
T. Michael Nork, University of Wisconsin
Theodore W. Randolph, University of Colorado
Kay D. Rittenhouse, Bausch & Lomb Pharmaceuticals
David Sherris, OXIGENE, Inc.
Ernst R. Tamm, University of Erlangen - Nuernberg
Carin Zimmerman, University of California San Francisco
 
Deadline for Abstracts: February 02, 2001
 
Registration: Registration fee includes lunch on the first day, refreshments and all documentation made available to us by speakers. Commercial registration is US $1099. Academic/government registration is US $699. The academic/government rate is extended to all participants registering as full time employees of government and universities. To receive the academic/government rate you must not be affiliated with any private organizations either as consultants or owners or part owners of businesses. Posterboard fee: US $45. On-site registration is an additional $100.

Payment: All payments must be made in U.S. funds drawn on a U.S. bank. Please make check(s) payable to The Knowledge Foundation, Inc. and attach to the registration form even if you have registered by phone, fax or e-mail. To guarantee your registration, payment must be received prior to the conference. Confirmation of your booking will follow.

E-mail: meder@knowledgefoundation.com
 
  Posted by:   Margit Eder  
Host: wks154.knowledgefoundation.com
   
 
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