IOVS Physiological Genomics
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Originally published In Press as doi:10.1167/iovs.08-2182 on May 30, 2008
 (Investigative Ophthalmology and Visual Science. 2008;49:4188-4194.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.08-2182
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Attenuation of Vision Loss and Delay in Apoptosis of Photoreceptors Induced by Proinsulin in a Mouse Model of Retinitis Pigmentosa

Silvia Corrochano,1 Rima Barhoum,2 Patricia Boya,1 Ana I. Arroba,1 Natalia Rodríguez-Muela,1 Violeta Gómez-Vicente,1 Fátima Bosch,3 Flora de Pablo,1 Pedro de la Villa,2 and Enrique J. de la Rosa1

1From the 3D Lab (Development, Differentiation, and Degeneration), Department of Cellular and Molecular Physiopathology, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain; the 2Department of Physiology, Universidad de Alcalá, Alcalá de Henares, Spain; and 3Department of Biochemistry and Molecular Biology, Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra, Spain.

PURPOSE. Retinitis pigmentosa (RP) is a heterogeneous group of inherited conditions that lead to blindness and for which there is no effective therapy. Apoptosis of photoreceptors is a common feature in animal models of the disease. Thus, the authors studied the therapeutic potential of proinsulin, an antiapoptotic molecule active during retinal development.

METHODS. Transgenic mice expressing human proinsulin (hPi) in the skeletal muscle were generated in a mixed C57BL/6:SJL background and were back-crossed to a C57BL/6 background. Two independent lineages of transgenic mice were established in which hPi production in muscle was constitutive and not regulated by glucose levels. hPi levels in serum, muscle, and retina were determined with a commercial ELISA kit, visual function was evaluated by electroretinographic (ERG) recording, and programmed cell death was assessed by TUNEL. Immunohistochemistry was used to evaluate retinal structure preservation and oxidative damage.

RESULTS. Transgenic expression of hPi in the rd10 retinal degeneration mouse model led to prolonged vision, as determined by ERG recording, in a manner that was related to the level of transgene expression. This attenuation of visual deterioration was correlated with a delay in photoreceptor apoptosis and with the preservation of retinal cytoarchitecture, particularly that of the cones.

CONCLUSIONS. These results provide a new basis for possible therapies to counteract retinitis pigmentosa and a new tool to characterize the mechanisms involved in the progress of retinal neurodegeneration.






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