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.

Combination of cGMP analogue and drug delivery system provides functional protection in hereditary retinal degeneration / 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, H. -G.; Gaillard, P.; Marigo, V.; Ekström, P.; Paquet-Durand, F.. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - 115:(2018), pp. E2997-E3006. [10.1073/pnas.1718792115]

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

Vighi E.
Formal Analysis
;
Hoffmann D.
Data Curation
;
Bertolotti E.
Data Curation
;
Marigo V.
Conceptualization
;
2018

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.
12-mar-2018
115
E2997
E3006
Combination of cGMP analogue and drug delivery system provides functional protection in hereditary retinal degeneration / 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, H. -G.; Gaillard, P.; Marigo, V.; Ekström, P.; Paquet-Durand, F.. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - 115:(2018), pp. E2997-E3006. [10.1073/pnas.1718792115]
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, H. -G.; Gaillard, P.; Marigo, V.; Ekström, P.; Paquet-Durand, F.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1156816
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