Combination of cGMP analogue and drug delivery system provides functional protection in hereditary retinal degeneration.

Abstract:

:Inherited retinal degeneration (RD) is a devastating and currently untreatable neurodegenerative condition that leads to loss of photoreceptor cells and blindness. The vast genetic heterogeneity of RD, the lack of "druggable" targets, and the access-limiting blood-retinal barrier (BRB) present major hurdles toward effective therapy development. Here, we address these challenges (i) by targeting cGMP (cyclic guanosine- 3',5'-monophosphate) signaling, a disease driver common to different types of RD, and (ii) by combining inhibitory cGMP analogs with a nanosized liposomal drug delivery system designed to facilitate transport across the BRB. Based on a screen of several cGMP analogs we identified an inhibitory cGMP analog that interferes with activation of photoreceptor cell death pathways. Moreover, we found liposomal encapsulation of the analog to achieve efficient drug targeting to the neuroretina. This pharmacological treatment markedly preserved in vivo retinal function and counteracted photoreceptor degeneration in three different in vivo RD models. Taken together, we show that a defined class of compounds for RD treatment in combination with an innovative drug delivery method may enable a single type of treatment to address genetically divergent RD-type diseases.

authors

Vighi E,Trifunović D,Veiga-Crespo P,Rentsch A,Hoffmann D,Sahaboglu A,Strasser T,Kulkarni M,Bertolotti E,van den Heuvel A,Peters T,Reijerkerk A,Euler T,Ueffing M,Schwede F,Genieser HG,Gaillard P,Marigo V,Ekström P,Pa

doi

10.1073/pnas.1718792115

subject

Has Abstract

pub_date

2018-03-27 00:00:00

pages

E2997-E3006

issue

13

eissn

0027-8424

issn

1091-6490

pii

1718792115

journal_volume

115

pub_type

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