Document Detail


Proinsulin slows retinal degeneration and vision loss in the P23H rat model of retinitis pigmentosa.
MedLine Citation:
PMID:  23017108     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Laura Fernández-Sánchez; Pedro Lax; Carolina Isiegas; Eduard Ayuso; José M Ruiz; Pedro de la Villa; Fatima Bosch; Enrique J de la Rosa; Nicolás Cuenca
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-11-05
Journal Detail:
Title:  Human gene therapy     Volume:  23     ISSN:  1557-7422     ISO Abbreviation:  Hum. Gene Ther.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-13     Completed Date:  2013-06-05     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  9008950     Medline TA:  Hum Gene Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1290-300     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Animals, Genetically Modified
Blindness / physiopathology,  prevention & control
Dendrites / drug effects,  physiology
Dependovirus / genetics
Disease Models, Animal
Electroretinography
Genetic Therapy / methods*
Humans
Photoreceptor Cells, Vertebrate / pathology
Proinsulin / blood,  genetics*,  pharmacology*
Rats
Retinal Bipolar Cells / pathology
Retinal Degeneration / genetics,  physiopathology,  therapy*
Retinitis Pigmentosa / genetics,  physiopathology*,  therapy*
Chemical
Reg. No./Substance:
9035-68-1/Proinsulin
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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