Proinsulin slows retinal degeneration and vision loss in the P23H rat model of retinitis pigmentosa

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Títol: Proinsulin slows retinal degeneration and vision loss in the P23H rat model of retinitis pigmentosa
Autors: Fernández Sánchez, Laura | Lax, Pedro | Isiegas, Carolina | Ayuso, Eduard | Ruiz Moreno, José María | Villa Polo, Pedro de la | Bosch, Fatima | Rosa Cano, Enrique J. de la | Cuenca, Nicolás
Grups d'investigació o GITE: Neurobiología del Sistema Visual y Terapia de Enfermedades Neurodegenerativas (NEUROVIS)
Centre, Departament o Servei: Universidad de Alicante. Departamento de Fisiología, Genética y Microbiología
Paraules clau: Proinsulin | Therapeutic | Retinal degeneration | Vision loss | Retinitis pigmentosa
Àrees de coneixement: Biología Celular | Fisiología
Data de publicació: 12-de desembre-2012
Editor: Mary Ann Liebert, Inc.
Citació bibliogràfica: FERNÁNDEZ-SÁNCHEZ, Laura, et al. “Proinsulin slows retinal degeneration and vision loss in the P23H rat model of retinitis pigmentosa”. Human Gene Therapy. December 2012, 23(12): 1290-1300. doi:10.1089/hum.2012.067
Resum: Proinsulin has been characterized as a neuroprotective molecule. In this work we assess the therapeutic potential of proinsulin on photoreceptor degeneration, synaptic connectivity, and functional activity of the retina in the transgenic P23H rat, an animal model of autosomal dominant retinitis pigmentosa (RP). P23H homozygous rats received an intramuscular injection of an adeno-associated viral vector serotype 1 (AAV1) expressing human proinsulin (hPi+) or AAV1-null vector (hPi−) at P20. Levels of hPi in serum were determined by enzyme-linked immunosorbent assay (ELISA), and visual function was evaluated by electroretinographic (ERG) recording at P30, P60, P90, and P120. Preservation of retinal structure was assessed by immunohistochemistry at P120. Human proinsulin was detected in serum from rats injected with hPi+ at all times tested, with average hPi levels ranging from 1.1 nM (P30) to 1.4 nM (P120). ERG recordings showed an amelioration of vision loss in hPi+ animals. The scotopic b-waves were significantly higher in hPi+ animals than in control rats at P90 and P120. This attenuation of visual deterioration correlated with a delay in photoreceptor degeneration and the preservation of retinal cytoarchitecture. hPi+ animals had 48.7% more photoreceptors than control animals. Presynaptic and postsynaptic elements, as well as the synaptic contacts between photoreceptors and bipolar or horizontal cells, were preserved in hPi+ P23H rats. Furthermore, in hPi+ rat retinas the number of rod bipolar cell bodies was greater than in control rats. Our data demonstrate that hPi expression preserves cone and rod structure and function, together with their contacts with postsynaptic neurons, in the P23H rat. These data strongly support the further development of proinsulin-based therapy to counteract retinitis pigmentosa.
Patrocinadors: This research was supported by grants from MICINN (BFU2009-07793/BFI, RETICS RD07/0062/0012-0008, and SAF2010-21879), TRACE (PET08-0282), CDTI, ENISA (Pro-Retina Therapeutics SL) and FUNDALUCE.
URI: http://hdl.handle.net/10045/33398
ISSN: 1043-0342 (Print) | 1557-7422 (Online)
DOI: 10.1089/hum.2012.067
Idioma: eng
Tipus: info:eu-repo/semantics/article
Drets: This is a copy of an article published in Human Gene Therapy © 2012 Mary Ann Liebert, Inc.; Human Gene Therapy is available online at: http://online.liebertpub.com.
Revisió científica: si
Versió de l'editor: http://dx.doi.org/10.1089/hum.2012.067
Apareix a la col·lecció: INV - NEUROVIS - Artículos de Revistas

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