| 1. |
- Himawan, Erico, et al.
(författare)
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Drug delivery to retinal photoreceptors
- 2019
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Ingår i: Drug Discovery Today. - : Elsevier BV. - 1359-6446. ; 24:8, s. 1637-1643
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Forskningsöversikt (refereegranskat)abstract
- The photoreceptors of the retina are afflicted by diseases that still often lack satisfactory treatment options. Although suitable drugs might be available in some cases, the delivery of these compounds into the eye and across the blood–retinal barrier remains a significant challenge for therapy development. Here, we review the routes of drug administration to the retina and highlight different options for drug delivery to the photoreceptor cells.
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| 2. |
- Huang, Li, et al.
(författare)
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Efficient Delivery of Hydrophilic Small Molecules to Retinal Cell Lines Using Gel Core-Containing Solid Lipid Nanoparticles
- 2022
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Ingår i: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 14:1, s. 74-74
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we developed a novel solid lipid nanoparticle (SLN) formulation for drug delivery of small hydrophilic cargos to the retina. The new formulation, based on a gel core and composite shell, allowed up to two-fold increase in the encapsulation efficiency. The type of hydrophobic polyester used in the composite shell mixture affected the particle surface charge, colloidal stability, and cell internalization profile. We validated SLNs as a drug delivery system by performing the encapsulation of a hydrophilic neuroprotective cyclic guanosine monophosphate analog, previously demonstrated to hold retinoprotective properties, and the best formulation resulted in particles with a size of ±250 nm, anionic charge > −20 mV, and an encapsulation efficiency of ±60%, criteria that are suitable for retinal delivery. In vitro studies using the ARPE-19 and 661W retinal cell lines revealed the relatively low toxicity of SLNs, even when a high particle concentration was used. More importantly, SLN could be taken up by the cells and the release of the hydrophilic cargo in the cytoplasm was visually demonstrated. These findings suggest that the newly developed SLN with a gel core and composite polymer/lipid shell holds all the characteristics suitable for the drug delivery of small hydrophilic active molecules into retinal cells.
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| 3. |
- Marigo, Valeria, et al.
(författare)
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Modulation of cGMP-signalling to Prevent Retinal Degeneration
- 2019
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Ingår i: RSC Drug Discovery Series. - Cambridge : Royal Society of Chemistry. - 2041-3203. ; 2019-January:66, s. 88-98
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Tidskriftsartikel (refereegranskat)abstract
- In the photoreceptors of the retina, the second-messenger molecule cyclic guanosine monophosphate (cGMP) occupies centre stage in the phototransduction cascade. Remarkably, cGMP is also involved in hereditary photoreceptor degeneration caused by a variety of different genetic insults. This provides an entry point for the development of inhibitory cGMP analogues for a mutation-independent treatment. Here, we outline how cGMP signalling can be targeted for the treatment of retinal degeneration, how inhibitory cGMP analogues may be designed and formulated, and how test systems of rising complexity can be used to identify new compounds with photoreceptor neuroprotective properties. In this context, we cite the European Union-funded DRUGSFORD project and provide an example for the efficacy of a specific cGMP analogue to prevent photoreceptor loss and preserve retinal function.
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| 4. |
- Paquet-Durand, François, et al.
(författare)
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Modulation of Calcium Overload and Calpain Activity
- 2019
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Ingår i: RSC Drug Discovery Series. - Cambridge : Royal Society of Chemistry. - 2041-3203. ; 2019-January:66, s. 48-60
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Tidskriftsartikel (refereegranskat)abstract
- Fluxes of calcium ions (Ca2+) in rod photoreceptors are major regulators of steady-state and light-evoked intracellular reactions to stimuli. The homeostasis of Ca2+ is regulated by channels and pumps localized at the plasma membrane and in intracellular organelles. Photoreceptor degeneration is frequently associated with Ca2+ homeostasis disruption and stimulation of Ca2+ activated proteases, such as calpains. These events trigger molecular pathways leading to cell death. In this chapter we discuss Ca2+ channels and pumps as well as calpains as potential targets of new therapies for retinal degeneration.
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| 5. |
- Perez, Oswaldo, et al.
(författare)
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New Improved cGMP Analogues to Target Rod Photoreceptor Degeneration
- 2024
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society. - 0022-2623 .- 1520-4804. ; 67:10, s. 8396-
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Tidskriftsartikel (refereegranskat)abstract
- Retinitis pigmentosa (RP) is a form of retinal degeneration affecting a young population with an unmet medical need. Photoreceptor degeneration has been associated with increased guanosine 3′,5′-cyclic monophosphate (cGMP), which reaches toxic levels for photoreceptors. Therefore, inhibitory cGMP analogues attract interest for RP treatments. Here we present the synthesis of dithio-CN03, a phosphorodithioate analogue of cGMP, prepared using the H-phosphonothioate route. Two crystal modifications were identified as a trihydrate and a tetrahydrofuran monosolvates. Dithio-CN03 featured a lower aqueous solubility than its RP-phosphorothioate counterpart CN03, a drug candidate, and this characteristic might be favorable for sustained-release formulations aimed at retinal delivery. Dithio-CN03 was tested in vitro for its neuroprotective effects in photoreceptor models of RP. The comparison of dithio-CN03 to CN03 and its diastereomer SP-CN03, and to their phosphate derivative oxo-CN03 identifies dithio-CN03 as the compound with the highest efficacy in neuroprotection and thus as a promising new candidate for the treatment of RP.
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| 6. |
- Power, Michael, et al.
(författare)
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Cellular mechanisms of hereditary photoreceptor degeneration – Focus on cGMP
- 2020
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Ingår i: Progress in Retinal and Eye Research. - : Elsevier BV. - 1350-9462. ; 74
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Forskningsöversikt (refereegranskat)abstract
- The cellular mechanisms underlying hereditary photoreceptor degeneration are still poorly understood, a problem that is exacerbated by the enormous genetic heterogeneity of this disease group. However, the last decade has yielded a wealth of new knowledge on degenerative pathways and their diversity. Notably, a central role of cGMP-signalling has surfaced for photoreceptor cell death triggered by a subset of disease-causing mutations. In this review, we examine key aspects relevant for photoreceptor degeneration of hereditary origin. The topics covered include energy metabolism, epigenetics, protein quality control, as well as cGMP- and Ca2+-signalling, and how the related molecular and metabolic processes may trigger photoreceptor demise. We compare and integrate evidence on different cell death mechanisms that have been associated with photoreceptor degeneration, including apoptosis, necrosis, necroptosis, and PARthanatos. A special focus is then put on the mechanisms of cGMP-dependent cell death and how exceedingly high photoreceptor cGMP levels may cause activation of Ca2+-dependent calpain-type proteases, histone deacetylases and poly-ADP-ribose polymerase. An evaluation of the available literature reveals that a large group of patients suffering from hereditary photoreceptor degeneration carry mutations that are likely to trigger cGMP-dependent cell death, making this pathway a prime target for future therapy development. Finally, an outlook is given into technological and methodological developments that will with time likely contribute to a comprehensive overview over the entire metabolic complexity of photoreceptor cell death. Building on such developments, new imaging technology and novel biomarkers may be used to develop clinical test strategies, that fully consider the genetic heterogeneity of hereditary retinal degenerations, in order to facilitate clinical testing of novel treatment approaches.
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| 7. |
- Vighi, Eleonora, et al.
(författare)
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Combination of cGMP analogue and drug delivery system provides functional protection in hereditary retinal degeneration
- 2018
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 115:13, s. 2997-3006
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Tidskriftsartikel (refereegranskat)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.
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