Slowing and prevention of vision loss in Retinitis Pigmentosa of the 'Protein Logistics Disease' type

Abstract

Purpose : This approach addresses a group of Retinitis Pigmentosa (RP) forms that share a common pathophysiology of the 'Protein Logistics Disease' (PLD) type. PLD is a novel concept that links cell death in degenerative disorders with abnormal accumulation of misdirected proteins not reaching their target compartments. In this work, we investigate the therapeutic potential of a downregulation of rhodopsin to slow down or prevent vision loss in models of PLD type Retinitis Pigmentosa.

Methods : Two mouse lines with known defects in rod outer segment formation, the Prom1-/- (Zacchigna et al., J. Neurosci. 2009) and the rds +/- lines, served as models of PLD type Retinitis Pigmentosa. In both, excess rhodopsin is found in the entire cell body which we interpret as a sign of PLD. Both lines were cross-bred with rho-/- mice in order to generate Prom1-/- rho+/- and rds+/- rho+/- lines heterozygous for rhodopsin. Since the production of rhodopsin in rho+/- heterozygotes is close to 50% of normal, the effects of a reduced protein load on the development and severity of the PLD phenotype may be studied in comparison to the original lines. All four lines were thus examined for upto four months postnatally with in vivo diagnostics (electroretinography (ERG) and imaging) as well as ex vivo morphology and immunohistochemistry.

Results : Strikingly, the PLD lines additionally heterozygous for rhodopsin showed significantly less degeneration in comparison to their regular PLD counterparts. Over the period of examination, the outer retinae of Prom1-/- rho+/- mice remained about 50% thicker than those of the Prom1-/- mice, with about twice as many rows of rod nuclei remaining. Further, ERG responses were relatively well preserved in Prom1-/- rho+/- mice and b-wave amplitudes were about twice as high as those of Prom1-/- mice. The current results of the study in rds mice added later point in the same direction.

Conclusions : We show here that the downregulation of rhodopsin in photoreceptor cells has a strong beneficial effect on cell survival in RP forms of the PLD type, underlining that PLD may be a major factor in many retinal diseases that share aspects of the pathophysiological mechanism.
Our data further provide proof-of-concept for the therapeutic potential of interventional strategies to prevent aberrant distribution and accumulation of key disease-causing proteins in PLD type inherited retinal degenerations.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.