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Pharmaceutics
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Research Advances in RNA Therapeutics in France
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Research Advances in RNA Therapeutics in France

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

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 18699

Special Issue Editors

Prof. Dr. Chantal Pichon

E-Mail Website
Guest Editor
Center for Molecular Biophysics, (CBM, UPR 4301), Rue Charles Sadron, 45071 Orléans, France
Interests: gene delivery; mRNA therapeutics; chemical vectors; ultrasound assisted-delivery
Dr. Pascale Bouillé

E-Mail Website
Guest Editor
Flash Therapeutics, Parc technologique du Canal, 3 rue des satellites, 31400 Toulouse, France
Interests: gene delivery; DNA & RNA therapeutics; viral vectors; gene-editing; immunotherapy; regenerative medicine

Special Issue Information

Dear Colleagues,

The acquisition of knowledge on gene regulation and messenger RNA metabolism associated with biotechnological advances has enabled the development of therapeutic strategies based on various types of RNA molecules. With the approval of Patisiran, (ALN-TTR02) the first ever approved siRNA drug delivered by lipid nanocarriers and of mRNA-based anti-COVID 19 vaccines (BNT162b2 and mRNA-1273), we are witnessing the era of RNA-based therapies. To enable the development of these strategies, it is crucial to conduct global research that brings together the production and delivery of RNAs and associates them with the production of target cells in order to find the best combination to obtain optimal efficacy in different applications.

In France, several academic and private research teams are very active in the development of innovative RNA-based strategies for different applications such as gene editing, regenerative medicine and immunotherapy. This topical collection aims to share expertise and present research papers and review articles covering recent progress and achievements in RNA-based therapies from academic and industrial institutions covering recent progress and achievements in high-end RNA-based therapies.

Prof. Dr. Chantal Pichon
Dr. Pascale Bouillé
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

  • nanomedicine
  • virus like particles
  • physical delivery
  • silencing RNA
  • vaccines
  • messenger RNA
  • immunotherapy
  • gene editing
  • regenerative medicine
  • cell therapy

Published Papers (6 papers)

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Research

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16 pages, 4534 KiB  
Article
Comparison of Physicochemical Properties of LipoParticles as mRNA Carrier Prepared by Automated Microfluidic System and Bulk Method
by Camille Ayad, Altan Yavuz, Jean-Paul Salvi, Pierre Libeau, Jean-Yves Exposito, Valentine Ginet, Claire Monge, Bernard Verrier and Danielle Campiol Arruda
Pharmaceutics 2022, 14(6), 1297; https://doi.org/10.3390/pharmaceutics14061297 - 18 Jun 2022
Cited by 2 | Viewed by 2383
Abstract
Polymeric and/or lipid platforms are promising tools for nucleic acid delivery into cells. We previously reported a lipid–polymer nanocarrier, named LipoParticles, consisting of polylactic acid nanoparticles surrounded by cationic lipids, and allowing the addition of mRNA and cationic LAH4-1 peptide at their surface. [...] Read more.
Polymeric and/or lipid platforms are promising tools for nucleic acid delivery into cells. We previously reported a lipid–polymer nanocarrier, named LipoParticles, consisting of polylactic acid nanoparticles surrounded by cationic lipids, and allowing the addition of mRNA and cationic LAH4-1 peptide at their surface. Although this mRNA platform has shown promising results in vitro in terms of mRNA delivery and translation, the bulk method used to prepare LipoParticles relies on a multistep and time-consuming procedure. Here, we developed an automated process using a microfluidic system to prepare LipoParticles, and we compared it to the bulk method in terms of morphology, physicochemical properties, and ability to vectorize and deliver mRNA in vitro. LipoParticles prepared by microfluidic presented a smaller size and more regular spherical shape than bulk method ones. In addition, we showed that the total lipid content in LipoParticles was dependent on the method of preparation, influencing their ability to complex mRNA. LipoParticles decorated with two mRNA/LAHA-L1 ratios (1/20, 1/5) could efficiently transfect mouse DC2.4 cells except for the automated 1/5 assay. Moreover, the 1/5 mRNA/LAHA-L1 ratio drastically reduced cell toxicity observed in 1/20 ratio assays. Altogether, this study showed that homogeneous LipoParticles can be produced by microfluidics, which represents a promising platform to transport functional mRNA into cells. Full article
(This article belongs to the Special Issue Research Advances in RNA Therapeutics in France)
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16 pages, 2777 KiB  
Article
mRNA Lipoplexes with Cationic and Ionizable α-Amino-lipophosphonates: Membrane Fusion, Transfection, mRNA Translation and Conformation
by Sohail Akhter, Mathieu Berchel, Paul-Alain Jaffrès, Patrick Midoux and Chantal Pichon
Pharmaceutics 2022, 14(3), 581; https://doi.org/10.3390/pharmaceutics14030581 - 07 Mar 2022
Cited by 5 | Viewed by 2836
Abstract
Cationic liposomes are attractive carriers for mRNA delivery. Here, mRNA lipoplexes (LX) were prepared with the cationic lipids α-aminolipophosphonate (3b) or imidazolium lipophosphoramidate (2) associated with various α-aminolipophosphonates co-lipids comprising protonable groups (imidazole or pyridine) and DOPE. Physicochemical [...] Read more.
Cationic liposomes are attractive carriers for mRNA delivery. Here, mRNA lipoplexes (LX) were prepared with the cationic lipids α-aminolipophosphonate (3b) or imidazolium lipophosphoramidate (2) associated with various α-aminolipophosphonates co-lipids comprising protonable groups (imidazole or pyridine) and DOPE. Physicochemical parameters of liposomes and their membrane fusion activity were measured. LXs comprising either 3b- or 2- allowed transfection of ~25% and 40% of dendritic cells with low cytotoxicity, respectively; the efficiency increased up to 80% when 2 was combined with the imidazole-based co-lipid 1. The transfections were high with 3b/1, 3b/DOPE, 2/1 and 2/DOPE LXs. We observed that the transfection level was not well correlated with the acid-mediated membrane fusion activity of liposomes supposed to destabilize endosomes. The mRNA release from LXs and its translation capacity after release were studied for the most efficient LXs. The results showed that the more mRNA was condensed, the poorer the translation efficiency after release was. In contrast to DNA, circular dichroism performed on mRNA complexed with 2/DOPE revealed the presence of denatured mRNA in LXs explaining this lack of translation efficiency. This is an important parameter that should be stressed for the preparation of mRNA LXs with a conserved mRNA translation activity. Full article
(This article belongs to the Special Issue Research Advances in RNA Therapeutics in France)
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15 pages, 21108 KiB  
Article
Fate of Tableted Freeze-Dried siRNA Lipoplexes in Gastrointestinal Environment
by Asad Ur Rehman, Virginie Busignies, Marcela Coelho Silva Ribeiro, Nayara Almeida Lage, Pierre Tchoreloff, Virginie Escriou and Christine Charrueau
Pharmaceutics 2021, 13(11), 1807; https://doi.org/10.3390/pharmaceutics13111807 - 28 Oct 2021
Cited by 5 | Viewed by 2047
Abstract
The incorporation of siRNA into nanocarriers is mandatory to facilitate its intracellular delivery, as siRNA itself cannot enter cells. However, the incorporation of these nanocarriers into oral, solid dosage forms and their fate in the gastrointestinal environment is yet to be explored. In [...] Read more.
The incorporation of siRNA into nanocarriers is mandatory to facilitate its intracellular delivery, as siRNA itself cannot enter cells. However, the incorporation of these nanocarriers into oral, solid dosage forms and their fate in the gastrointestinal environment is yet to be explored. In the present work, the fate of, (i) naked siRNA, (ii) freshly prepared siRNA lipoplexes, and (iii) tableted siRNA lipoplexes, in simulated gastric and intestinal fluids was studied. The siRNA, either released from or protected within the lipoplexes, was quantified by gel electrophoresis and siRNA efficacy was assessed in cell transfection. The freshly prepared lipoplexes kept their siRNA load and transfection efficiency totally preserved during 1 h of incubation in simulated gastric fluid at 37 °C. However, in simulated intestinal fluid, despite no release of siRNA from lipoplexes after 6 h of incubation, gene silencing efficacy was dramatically decreased even after 1 h of exposure. The lipoplexes obtained from tablets efficiently protected siRNA in simulated gastric fluid, thus preserving the gene silencing efficacy, whereas their incubation in simulated intestinal fluid resulted in a marked siRNA release and decreased gene silencing efficacy. These results provided a detailed explanation for understanding the fate of siRNA in gastrointestinal conditions, when simply loaded in lipoplexes or formulated in the form of tablets. Full article
(This article belongs to the Special Issue Research Advances in RNA Therapeutics in France)
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Review

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25 pages, 1221 KiB  
Review
RNA-Based Strategies for Cell Reprogramming toward Pluripotency
by Anaëlle Bailly, Ollivier Milhavet and Jean-Marc Lemaitre
Pharmaceutics 2022, 14(2), 317; https://doi.org/10.3390/pharmaceutics14020317 - 28 Jan 2022
Cited by 7 | Viewed by 4663
Abstract
Cell therapy approaches to treat a wide range of pathologies have greatly benefited from cell reprogramming techniques that allow the conversion of a somatic cell into a pluripotent cell. Many technological developments have been made since the initial major discovery of this biological [...] Read more.
Cell therapy approaches to treat a wide range of pathologies have greatly benefited from cell reprogramming techniques that allow the conversion of a somatic cell into a pluripotent cell. Many technological developments have been made since the initial major discovery of this biological process. Recently reprogramming methods based on the use of RNA have emerged and seem very promising. Thus, in this review we will focus on presenting the interest of such methods for cell reprogramming but also how these RNA-based strategies can be extended to eventually lead to medical applications to improve healthspan and longevity. Full article
(This article belongs to the Special Issue Research Advances in RNA Therapeutics in France)
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21 pages, 972 KiB  
Review
Thinking Quantitatively of RNA-Based Information Transfer via Extracellular Vesicles: Lessons to Learn for the Design of RNA-Loaded EVs
by Max Piffoux, Jeanne Volatron, Amanda K. A. Silva and Florence Gazeau
Pharmaceutics 2021, 13(11), 1931; https://doi.org/10.3390/pharmaceutics13111931 - 15 Nov 2021
Cited by 10 | Viewed by 2398
Abstract
Extracellular vesicles (EVs) are 50–1000 nm vesicles secreted by virtually any cell type in the body. They are expected to transfer information from one cell or tissue to another in a short- or long-distance way. RNA-based transfer of information via EVs at long [...] Read more.
Extracellular vesicles (EVs) are 50–1000 nm vesicles secreted by virtually any cell type in the body. They are expected to transfer information from one cell or tissue to another in a short- or long-distance way. RNA-based transfer of information via EVs at long distances is an interesting well-worn hypothesis which is ~15 years old. We review from a quantitative point of view the different facets of this hypothesis, ranging from natural RNA loading in EVs, EV pharmacokinetic modeling, EV targeting, endosomal escape and RNA delivery efficiency. Despite the unique intracellular delivery properties endowed by EVs, we show that the transfer of RNA naturally present in EVs might be limited in a physiological context and discuss the lessons we can learn from this example to design efficient RNA-loaded engineered EVs for biotherapies. We also discuss other potential EV mediated information transfer mechanisms, among which are ligand–receptor mechanisms. Full article
(This article belongs to the Special Issue Research Advances in RNA Therapeutics in France)
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20 pages, 1721 KiB  
Review
miRNA Delivery by Nanosystems: State of the Art and Perspectives
by Fernanda C. Moraes, Chantal Pichon, Didier Letourneur and Frédéric Chaubet
Pharmaceutics 2021, 13(11), 1901; https://doi.org/10.3390/pharmaceutics13111901 - 09 Nov 2021
Cited by 33 | Viewed by 3289
Abstract
MicroRNAs (miRNAs) are short (~21–23 nucleotides), non-coding endogenous RNA molecules that modulate gene expression at the post-transcriptional level via the endogenous RNA interference machinery of the cell. They have emerged as potential biopharmaceuticals candidates for the treatment of various diseases, including cancer, cardiovascular [...] Read more.
MicroRNAs (miRNAs) are short (~21–23 nucleotides), non-coding endogenous RNA molecules that modulate gene expression at the post-transcriptional level via the endogenous RNA interference machinery of the cell. They have emerged as potential biopharmaceuticals candidates for the treatment of various diseases, including cancer, cardiovascular and metabolic diseases. However, in order to advance miRNAs therapeutics into clinical settings, their delivery remains a major challenge. Different types of vectors have been investigated to allow the delivery of miRNA in the diseased tissue. In particular, non-viral delivery systems have shown important advantages such as versatility, low cost, easy fabrication and low immunogenicity. Here, we present a general overview of the main types of non-viral vectors developed for miRNA delivery, with their advantages, limitations and future perspectives. Full article
(This article belongs to the Special Issue Research Advances in RNA Therapeutics in France)
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