Proinsulin Delays Retinal Degeneration and Vision Loss in the P23H Rat

Abstract

 

Purpose:

 

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal degenerations that lead to blindness and for which there is no effective therapy. Photoreceptor cell death is a major hallmark in RP patients and in animal models of the disease. Previous studies have shown that transgenic and AAV-mediated expression of the antiapoptotic molecule proinsulin delays retinal degeneration in the rd10 mouse model of RP. The objective of this study is to assess the therapeutic potential of proinsulin in the P23H rat model of RP.

 

Methods:

 

An adeno-associated viral vector serotype 1 (AAV2/1) expressing human proinsulin (hPi) under the control of the cytomegalovirus (CMV) promoter has been generated. P23H homozygous (line 3) rats have received an intramuscular injection of AAV2/1-hPi (hPi+) or AAV2/1-null (hPi-) vector at P20. In these rats, levels of hPi in serum have been determined by ELISA, and visual function has been evaluated by electroretinographic (ERG) recording at P30, P60, P90 and P120. Preservation of retinal structure has been assessed by immunohistochemistry at P120.

 

Results:

 

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. Thus, the scotopic b-waves were significantly higher in hPi+ animals than in control hPi- rats at P90 and P120 (p<0.05 and p<0.01, respectively; ANOVA). This attenuation of visual deterioration correlated with a delay in photoreceptor degeneration and the preservation of retinal cytoarchitecture.

 

Conclusions:

 

Our data demonstrate that hPi expression attenuates the retinal degeneration and the loss of retinal function in the P23H rat. Notably, these results constitute additional proof of concept of what we have previously observed in a different animal model of RP. All together, these data lay solid grounds to develop a proinsulin-based therapy to treat retinitis pigmentosa.

 

Keywords: neuroprotection • retina • adenovirus