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Advances in the Delivery of DNA and RNA Therapeutics to the Eye

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Gene and Cell Therapy".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 13741

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Special Issue Editors

Assist. Prof. Marika Ruponen

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Guest Editor

School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70210 Kuopio, Finland
Interests: drug and gene delivery; nanomedicines; ocular pharmacokinetics; intracellular kinetics

Senior Researcher Astrid Subrizi

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Guest Editor

School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70210 Kuopio, Finland
Interests: ocular drug targeting; drug and gene delivery; RNAi therapy; ocular pharmacokinetics; ocular barriers

Special Issue Information

Dear Colleagues,

The eye is an appealing target organ for DNA- and RNA-based therapies and has been at the forefront of translational gene therapy for many years. The eye is enclosed and relatively immune privileged due to an efficient blood–retina barrier and little lymphatic drainage. These characteristics decrease the likelihood of systemic toxicity and allow local treatment with smaller doses. Non-invasive in vivo imaging techniques permit long-term monitoring of treatment. Viral-based vectors are currently the most promising option for gene replacement or correction in the treatment of inherited retinal diseases. Viral vectors, however, require invasive subretinal injections, and concerns related to their safety, repeated dosing, and large-scale production have been only partially addressed. For this reason, non-viral alternatives should be considered and explored. Research in this field has expanded to find solutions for prolonged expression of therapeutic proteins or gene silencing in the treatment of more common non-genetic retinal diseases, such as age-related macular degeneration. Other research efforts include the development of delivery strategies that allow the retinal administration of DNA and RNA therapeutics via less invasive and safer routes, such as intravitreal, periocular, or systemic delivery.

The goal of this Special Issue is to highlight the current progress in the field of ocular delivery of DNA and RNA therapeutics.

Assist. Prof. Marika Ruponen
Senior Researcher Astrid Subrizi
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

gene therapy
RNA-based drugs
non-viral vectors
viral vectors
ocular barriers
ocular administration routes
retina

Published Papers (4 papers)

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Research

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23 pages, 4210 KiB

Open AccessArticle

Efficient Ocular Delivery of VCP siRNA via Reverse Magnetofection in RHO P23H Rodent Retina Explants

by Merve Sen, Marco Bassetto, Florent Poulhes, Olivier Zelphati, Marius Ueffing and Blanca Arango-Gonzalez

Pharmaceutics 2021, 13(2), 225; https://doi.org/10.3390/pharmaceutics13020225 - 6 Feb 2021

Cited by 10 | Viewed by 3099

Abstract

The use of synthetic RNA for research purposes as well as RNA-based therapy and vaccination has gained increasing importance. Given the anatomical seclusion of the eye, small interfering RNA (siRNA)-induced gene silencing bears great potential for targeted reduction of pathological gene expression that may allow rational treatment of chronic eye diseases in the future. However, there is yet an unmet need for techniques providing safe and efficient siRNA delivery to the retina. We used magnetic nanoparticles (MNPs) and magnetic force (Reverse Magnetofection) to deliver siRNA/MNP complexes into retinal explant tissue, targeting valosin-containing protein (VCP) previously established as a potential therapeutic target for autosomal dominant retinitis pigmentosa (adRP). Safe and efficient delivery of VCP siRNA was achieved into all retinal cell layers of retinal explants from the RHO P23H rat, a rodent model for adRP. No toxicity or microglial activation was observed. VCP silencing led to a significant decrease of retinal degeneration. Reverse Magnetofection thus offers an effective method to deliver siRNA into retinal tissue. Used in combination with retinal organotypic explants, it can provide an efficient and reliable preclinical test platform of RNA-based therapy approaches for ocular diseases. Full article

(This article belongs to the Special Issue Advances in the Delivery of DNA and RNA Therapeutics to the Eye)

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18 pages, 2970 KiB

Open AccessArticle

Vaccinia Virus Protein B18R: Influence on mRNA Immunogenicity and Translation upon Non-Viral Delivery in Different Ocular Cell Types

by An-Katrien Minnaert, Joke Devoldere, Karen Peynshaert, Laure Vercruysse, Stefaan C. De Smedt and Katrien Remaut

Pharmaceutics 2021, 13(1), 74; https://doi.org/10.3390/pharmaceutics13010074 - 7 Jan 2021

Cited by 4 | Viewed by 3120

Abstract

In the last few years, interest has grown in the use of nucleic acids as an ocular therapy for retinal genetic diseases. Recently, our research group has demonstrated that mRNA delivery could result in effective protein expression in ocular cells following subretinal injection. Yet, although mRNA therapy comes with many advantages, its immunogenicity resulting in hampered mRNA translation delays development to the clinic. Therefore, several research groups investigate possible strategies to reduce this innate immunity. In this study, we focus on B18R, an immune inhibitor to suppress the mRNA-induced innate immune responses in two ocular cell types. We made use of retinal pigment epithelial (RPE) cells and Müller cells both as immortalized cell lines and primary bovine cells. When cells were co-incubated with both B18R and mRNA-MessengerMAX lipoplexes we observed an increase in transfection efficiency accompanied by a decrease in interferon-β production, except for the Müller cells. Moreover, uptake efficiency and cell viability were not hampered. Taken together, we showed that the effect of B18R is cell type-dependent but remains a possible strategy to improve mRNA translation in RPE cells. Full article

(This article belongs to the Special Issue Advances in the Delivery of DNA and RNA Therapeutics to the Eye)

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17 pages, 7319 KiB

Open AccessArticle

Avoiding the Pitfalls of siRNA Delivery to the Retinal Pigment Epithelium with Physiologically Relevant Cell Models

by Eva Ramsay, Manuela Raviña, Sanjay Sarkhel, Sarah Hehir, Neil R. Cameron, Tanja Ilmarinen, Heli Skottman, Jørgen Kjems, Arto Urtti, Marika Ruponen and Astrid Subrizi

Pharmaceutics 2020, 12(7), 667; https://doi.org/10.3390/pharmaceutics12070667 - 16 Jul 2020

Cited by 7 | Viewed by 3163

Abstract

Inflammation is involved in the pathogenesis of several age-related ocular diseases, such as macular degeneration (AMD), diabetic retinopathy, and glaucoma. The delivery of anti-inflammatory siRNA to the retinal pigment epithelium (RPE) may become a promising therapeutic option for the treatment of inflammation, if the efficient delivery of siRNA to target cells is accomplished. Unfortunately, so far, the siRNA delivery system selection performed in dividing RPE cells in vitro has been a poor predictor of the in vivo efficacy. Our study evaluates the silencing efficiency of polyplexes, lipoplexes, and lipidoid-siRNA complexes in dividing RPE cells as well as in physiologically relevant RPE cell models. We find that RPE cell differentiation alters their endocytic activity and causes a decrease in the uptake of siRNA complexes. In addition, we determine that melanosomal sequestration is another significant and previously unexplored barrier to gene silencing in pigmented cells. In summary, this study highlights the importance of choosing a physiologically relevant RPE cell model for the selection of siRNA delivery systems. Such cell models are expected to enable the identification of carriers with a high probability of success in vivo, and thus propel the development of siRNA therapeutics for ocular disease. Full article

(This article belongs to the Special Issue Advances in the Delivery of DNA and RNA Therapeutics to the Eye)

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Review

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22 pages, 882 KiB

Open AccessReview

Viral-Vector-Delivered Anti-Angiogenic Therapies to the Eye

by Sanna Koponen, Emmi Kokki, Kati Kinnunen and Seppo Ylä-Herttuala

Pharmaceutics 2021, 13(2), 219; https://doi.org/10.3390/pharmaceutics13020219 - 5 Feb 2021

Cited by 9 | Viewed by 3747

Abstract

Pathological vessel growth harms vision and may finally lead to vision loss. Anti-angiogenic gene therapy with viral vectors for ocular neovascularization has shown great promise in preclinical studies. Most of the studies have been conducted with different adeno-associated serotype vectors. In addition, adeno- and lentivirus vectors have been used. Therapy has been targeted towards blocking vascular endothelial growth factors or other pro-angiogenic factors. Clinical trials of intraocular gene therapy for neovascularization have shown the treatment to be safe without severe adverse events or systemic effects. Nevertheless, clinical studies have not proceeded further than Phase 2 trials. Full article

(This article belongs to the Special Issue Advances in the Delivery of DNA and RNA Therapeutics to the Eye)

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