transferrin and ocular therapy – oculotransferrine

ABSTRACT

Retinal degeneration has been associated with iron accumulation in age related macular degeneration (AMD) and in several rodent models which had one or several iron regulating proteins impairment. All cells require iron for survival and as a cofactor of a variety of enzymes ( However, it is also highly toxic due to its ability to generate free radicals via the Fenton reaction.Transferrin (Tf) expression, a main participant in iron homeostasis , is enhanced in aging human retina. We investigated iron concentration and the protective role of human Tf (hTf) in Rd10 mice, a model of retinal degeneration.Pixe analysis demonstrated an age-dependent iron accumulation in photoreceptors in Rd10 mice. A new mice was derived the Rd10/hTf mice which had the Rd10 mutation and expressed hTf at highly level. These mice showed a decrease in the photoreceptors (PR) death and a preservation of rods and cones. Ip injection hTf in RD10 mice resulted by hTf presence in mice retina and PR degeneration was considerably reduced in a dose-dependent manner. In Rd10 mice, hTf expressed by genetic modification or ip injected permitted to rescue PR from degeneration. Similar results were obtained by ip injection of Tf in the RCS rat a model of retinitis pigmentosum.This study highlights the therapeutical potential of Tf in degenerative disease like in retinitis pigmentosa or AMD.
The project is- 1- to determine the optimal conditions of Tf delivery in the eye of Rd10 mice ,RCS rat and P23H rat a model of retinitis pigmentosum by IVT injection , a technic which could be applied to human treatment since it is currently used to treat exsudative AMD with VEGF monoclonal antibodies. 2- to tranfect directly the ciliary muscle with plasmids carrying the Tf gene or part of it and to assess the extent and duration of protection of the retina . This technic has been discovered in the laboratory by DR F. Behar Cohen and successfully applied to various experimental models of retinal inflammation. 3- to discover the natural regulators of Tf activity in order to enhance its neurotrophic properties and its rôle in regulating RPE phagocytosis.
These data would provide the basis for licensing the process or other industrial developments