Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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

Vighi, Eleonora ; Trifunovic, Dragana ; Veiga-Crespo, Patricia LU ; Rentsch, Andreas ; Hoffmann, Dorit ; Sahaboglu, Ayse ; Strasser, Torsten ; Kulkarni, Manoj ; Bertolotti, Evelina and Van Den Heuvel, Angelique , et al. (2018) In Proceedings of the National Academy of Sciences of the United States of America 115(13). p.2997-3006
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Apoptosis, Calpain, CNG channel, In vivo imaging, PKG
in
Proceedings of the National Academy of Sciences of the United States of America
volume
115
issue
13
pages
2997 - 3006
publisher
National Academy of Sciences
external identifiers
  • pmid:29531030
  • scopus:85044431243
ISSN
0027-8424
DOI
10.1073/pnas.1718792115
language
English
LU publication?
yes
id
8f1ca54b-0068-4f27-be30-8c56998048b3
date added to LUP
2018-05-23 12:31:30
date last changed
2025-02-04 12:30:43
@article{8f1ca54b-0068-4f27-be30-8c56998048b3,
  abstract     = {{<p>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.</p>}},
  author       = {{Vighi, Eleonora and Trifunovic, Dragana and Veiga-Crespo, Patricia and Rentsch, Andreas and Hoffmann, Dorit and Sahaboglu, Ayse and Strasser, Torsten and Kulkarni, Manoj and Bertolotti, Evelina and Van Den Heuvel, Angelique and Peters, Tobias and Reijerkerk, Arie and Euler, Thomas and Ueffing, Marius and Schwede, Frank and Genieser, Hans Gottfried and Gaillard, Pieter and Marigo, Valeria and Ekström, Per and Paquet-Durand, François}},
  issn         = {{0027-8424}},
  keywords     = {{Apoptosis; Calpain; CNG channel; In vivo imaging; PKG}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{13}},
  pages        = {{2997--3006}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{Combination of cGMP analogue and drug delivery system provides functional protection in hereditary retinal degeneration}},
  url          = {{http://dx.doi.org/10.1073/pnas.1718792115}},
  doi          = {{10.1073/pnas.1718792115}},
  volume       = {{115}},
  year         = {{2018}},
}