Übersicht
colloquia - [ 21.02.2007 (11.00) ]
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"Diseases caused by defects in the Visual Cycle: Retinoids as Potential Therapeutic Agents of Childhood Blindness"
Sprecher: Professor Dr. Krzysztof Palczewski, Case Western Reserve University, USA
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Abstract (by author)
Blindness and approaches:
Promises of therapy for incurable blinding hereditary retinal diseases are more frequently discussed owing to major scientific advances that have increased our understanding of basic disease mechanisms. For example, childhood-onset inherited retinal degeneration is one of the more devastating blinding diseases. Either shortly after birth or in the first few years of life, parents note that a child is not responding visually in a normal way (e.g., severe nystagmus). This finding usually leads to a succession of clinical opinions and an eventual diagnosis such as Leber congenital amaurosis (LCA), early-onset retinitis pigmentosa or related designation, which manifest among other characteristics by a severely abnormal electroretinogram (ERG). These diseases remain without treatment. Greater understanding of the basis of this genetically heterogeneous group of early-onset disorders has occurred in recent years, because molecular genetic studies have revealed causative genes. Mutations in the retinal pigment epithelial (RPE) genes encoding RPE65 is one of the four known molecular causes of these blinding diseases. Several therapeutic approaches to treat LCA have been proposed: RPE transplantation, gene replacement therapy, and pharmacological intervention. Recently, we and our collaborator Dr. Jacobson, reported on the pharmacological treatment of the mouse model of the disease. Specifically, we demonstrated that the biochemical defect could be bypassed using oral administration of a cis-retinoid. This experiment led to a remarkable change in retinal biochemistry and function in the mutant animals. At 48 hours post-treatment, visual pigment is formed and retinal function dramatically improved. This pharmacological experiment can now form the basis for treatment of similar forms of childhood blindness. The normal function of the visual pigment in animals persists for at least 8 months after a single dose, and is therefore appealing for human treatment.
Another devastating eye disease is age-related macular degeneration (AMD). More than 200,000 Americans become legally blind in one eye and 35,000 lose vision in the second eye each year. This number is on the rise, with the increase in life expectancy and population over the age of 60. Since animal models currently are of limited value for this disease, one of the better methods of study has involved the comparison of affected individuals with age-matched controls. However, recent advancements in the genetics of AMD lay the groundwork for more fundamental research on the pathogenesis of the disease at the molecular level. However, in contrast to single gene-related diseases, the multifactorial and progressive nature of AMD requires a novel multidisciplinary team approach. We would like to test the hypothesis that a subtle change in the retinoid flow and rhodopsin regeneration, over time, result in abnormal metabolism and/or catabolism within the RPE resulting in the inability of the cell to eliminate waste products and the build up of drusen in the basal membrane of the RPE cells. The succession of events would involve recruitment of macrophages, increase local concentration of cytokines, up-regulation of vascular endothelial growth factor within endothelial cells and other cell types, and finally the formation of choroidal neovascular membranes, the hallmark of wet AMD.
Bibliographisches zu dem Referenten/Referentin finden Sie unter:
http://pharmacology.case.edu/department/faculty/palczewski/index.htlm
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Ort:
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Parken:
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Contact:
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EML Research gGmbH
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69118 Heidelberg
Phone: +49 (0)6221 - 533 - 201
Fax: +49 (0)6221 - 533 - 298
Email: [email protected]
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