Journal Article

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

Schwede, Frank, Veiga-Crespo, Patricia, Trifunović, Dragana, Bertolotti, Evelina, Peters, Tobias, Ueffing, Marius, Sahaboglu, Ayse, Paquet-Durand, François, Vighi, Eleonora, Strasser, Torsten, Euler, Thomas, Kulkarni, Manoj, Reijerkerk, Arie, Ekström, Per, van den Heuvel, Angelique, Genieser, Hans-Gottfried, Gaillard, Pieter, Rentsch, Andreas, Hoffmann, Dorit, Marigo, Valeria

2018

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Analogs / Animals / Apoptosis / Biological Sciences / Blindness / Blood-Retinal Barrier - drug effects / Blood-Retinal Barrier - metabolism / Cell activation / Cell death / Chemistry / Clinical Medicine / Cyclic GMP / Cyclic GMP - administration & dosage / Cyclic GMP - analogs & derivatives / Cyclic GMP - pharmacology / Cyclic GMP-Dependent Protein Kinases - metabolism / Degeneration / Disease Models, Animal / Drug delivery / Drug Delivery Systems / Drug therapy / Eye diseases / Guanosine / Heterogeneity / Klinisk medicin / Liposomes / Medical and Health Sciences / Medicin och hälsovetenskap / Mice / Neurodegeneration / Neuroscience / Oftalmologi / Ophthalmology / Pharmacology / Photoreceptor Cells - metabolism / Physical Sciences / PNAS Plus / Retina / Retina - drug effects / Retina - metabolism / Retinal degeneration / Retinal Degeneration - drug therapy / Retinal Degeneration - metabolism / Signal Transduction - drug effects