TY - JOUR
T1 - Combination of cGMP analogue and drug delivery system provides functional protection in hereditary retinal degeneration
AU - Vighi, Eleonora
AU - Trifunovic, Dragana
AU - Veiga-Crespo, Patricia
AU - Rentsch, Andreas
AU - Hoffmann, Dorit
AU - Sahaboglu, Ayse
AU - Strasser, Torsten
AU - Kulkarni, Manoj
AU - Bertolotti, Evelina
AU - Van Den Heuvel, Angelique
AU - Peters, Tobias
AU - Reijerkerk, Arie
AU - Euler, Thomas
AU - Ueffing, Marius
AU - Schwede, Frank
AU - Genieser, Hans Gottfried
AU - Gaillard, Pieter
AU - Marigo, Valeria
AU - Ekström, Per
AU - Paquet-Durand, François
PY - 2018/3/27
Y1 - 2018/3/27
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Calpain
KW - CNG channel
KW - In vivo imaging
KW - PKG
U2 - 10.1073/pnas.1718792115
DO - 10.1073/pnas.1718792115
M3 - Article
C2 - 29531030
AN - SCOPUS:85044431243
SN - 0027-8424
VL - 115
SP - E2997-E3006
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 13
ER -