Combination of cGMP analogue and drug delivery system provides functional protection in hereditary retinal degeneration
| Autor: | Andreas Rentsch, Manoj Kulkarni, Dorit Hoffmann, Marius Ueffing, Dragana Trifunović, François Paquet-Durand, Angelique van den Heuvel, Patricia Veiga-Crespo, Thomas Euler, Eleonora Vighi, Arie Reijerkerk, Torsten Strasser, Pieter J. Gaillard, Frank Schwede, Valeria Marigo, Evelina Bertolotti, Per Ekström, Tobias Peters, Ayse Sahaboglu, Hans G. Genieser |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Retinal degeneration Druggability Pharmacology Photoreceptor cell Retina 03 medical and health sciences Mice Drug Delivery Systems In vivo Blood-Retinal Barrier medicine Cyclic GMP-Dependent Protein Kinases Animals Photoreceptor Cells Cyclic GMP Multidisciplinary biology business.industry Retinal Degeneration PKG apoptosis Calpain Biological Sciences CNG channel medicine.disease Disease Models Animal Chemistry 030104 developmental biology medicine.anatomical_structure Targeted drug delivery PNAS Plus Apoptosis Drug delivery Liposomes Physical Sciences biology.protein sense organs in vivo imaging business calpain Signal Transduction Neuroscience |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 |
| Popis: | Significance Development of treatments for hereditary degeneration of the retina (RD) is hampered by the vast genetic heterogeneity of this group of diseases and by the delivery of the drug to an organ protected by the blood–retina barrier. Here, we present an approach for the treatment of different types of RD, combining an innovative drug therapy with a liposomal system that facilitates drug delivery into the retina. Using different animal models of RD we show that this pharmacological treatment preserved both the viability of cells in the retina as well as retinal function. Thus, our study provides an avenue for the development of therapies for hereditary diseases which cause blindness, an unmet medical need. 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|