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

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Title: Proinsulin slows retinal degeneration and vision loss in the P23H rat model of retinitis pigmentosa
Authors: 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
Research Group/s: Neurobiología del Sistema Visual y Terapia de Enfermedades Neurodegenerativas (NEUROVIS)
Center, Department or Service: Universidad de Alicante. Departamento de Fisiología, Genética y Microbiología
Keywords: Proinsulin | Therapeutic | Retinal degeneration | Vision loss | Retinitis pigmentosa
Knowledge Area: Biología Celular | Fisiología
Issue Date: 12-Dec-2012
Publisher: Mary Ann Liebert, Inc.
Citation: 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
Abstract: 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.
Sponsor: 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
Language: eng
Type: info:eu-repo/semantics/article
Rights: 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.
Peer Review: si
Publisher version: http://dx.doi.org/10.1089/hum.2012.067
Appears in Collections:INV - NEUROVIS - Artículos de Revistas

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