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Pharmaceutics
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State-of-Art in mRNA Therapeutics and Gene Delivery
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State-of-Art in mRNA Therapeutics and Gene Delivery

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

Deadline for manuscript submissions: closed (20 August 2024) | Viewed by 14483

Special Issue Editor

Dr. Liliana Mendonca

E-Mail Website
Guest Editor
1. CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
2. CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
Interests: gene and cell therapy; advanced therapy medicinal products; viral and non-viral vectors for gene delivery; cell reprogramming; cell transplantation; brain regeneration

Special Issue Information

Dear Colleagues,

We are pleased to invite you to participate in this Special Issue, entitled “State-of-the-Art in mRNA Therapeutics and Gene Delivery”. mRNA therapeutics are a new class of drugs and therapeutic strategies based on the insertion of a specific genetic message (mRNA) into the cells and the silencing or gene editing of a specific mRNA. There are several tools available to trigger these mechanisms, such as IVT mRNA, siRNA, shRNA, and miRNA. Given the fast degradation and low intrinsic cell delivery efficiency that some of these molecules exhibit, gene delivery vectors play a very significant role in the therapeutic efficiency of mRNA-based therapies. There are two main groups of delivery vectors: viral vectors, such as the lentiviral and adeno-associated viral particles; and non-viral vectors, such as lipid- and polymer-based nanoparticles. Numerous preclinical studies and some clinical trials based on mRNA therapeutics were launched with the aim of treating  various human diseases, and applied to fields such as cancer immunotherapy, infectious disease vaccines, protein replacement, genome engineering, and the genetic reprogramming of cells.

This Special Issue aims to provide an overview of the current state of mRNA-based therapeutics, namely the available therapeutic molecules and delivery vectors, their modes of action, and the preclinical and clinical testing of new mRNA-based therapeutics. This issue will cover some of the main critical aspects of mRNA-based therapeutics development; the latest advances, challenges and strengths; and various experimental and therapeutic applications.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following:

  • Advances in mRNA-based gene therapy;
  • Therapeutic oligonucleotides;
  • Short-hairpin RNA (shRNA), small interfering RNA (siRNA), microRNA (miRNA), small activating RNA (saRNA), exon-skipping antisense oligonucleotides;
  • In vitro transcribed (IVT) mRNA, mRNA-based protein replacement therapy, mRNA-based vaccines, mRNA-mediated antibody expression;
  • The preclinical development and clinical testing of tools and techniques for mRNA-based therapies;
  • The preclinical development and clinical testing of non-viral and viral vectors for mRNA-based therapies delivery.

We look forward to receiving your contributions.

Dr. Liliana Mendonca
Guest Editor

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
  • mRNA-mediated gene silencing, expression, and editing
  • shRNA, siRNA, miRNA, saRNA, oligonucleotides
  • nucleic acid therapeutics
  • viral and non-viral vectors
  • lipid-, polymer-, and peptide-based nanoparticles
  • gene delivery
  • preclinical and clinical development of RNA therapeutics

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Further information on MDPI's Special Issue polices can be found here.

Published Papers (6 papers)

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Research

15 pages, 2776 KiB  
Article
Development of Biolayer Interferometry (BLI)-Based Double-Stranded RNA Detection Method with Application in mRNA-Based Therapeutics and Vaccines
by Dharia Sara Silas, Bindiya Juneja, Keerat Kaur, Muralikrishna Narayanareddy Gari, Yingjian You, Youmi Moon, Yizhuo Chen, Srishti Arora, Johanna Hansen, Kathir Muthusamy, Yue Fu, Nisha Palackal and Erica A. Pyles
Pharmaceutics 2024, 16(9), 1227; https://doi.org/10.3390/pharmaceutics16091227 - 19 Sep 2024
Viewed by 1697
Abstract
Background: In vitro-transcribed (IVT) mRNA has been established as a promising platform for therapeutics and vaccine development. Double-stranded RNA (dsRNA) is a major impurity of IVT mRNA and can trigger unfavored immune responses, potentially causing adverse events in patients. Existing dsRNA detection and [...] Read more.
Background: In vitro-transcribed (IVT) mRNA has been established as a promising platform for therapeutics and vaccine development. Double-stranded RNA (dsRNA) is a major impurity of IVT mRNA and can trigger unfavored immune responses, potentially causing adverse events in patients. Existing dsRNA detection and quantitation methods, such as gel electrophoresis, ELISA, or homogeneous time-resolved fluorescence (HTRF), have low sensitivity or are time-consuming. A recently published lateral flow immunoassay (LFSA) was shown to be fast, but it lacks the sensitivity for dsRNA with uridine modifications. Methods: In this study, we provided a possible explanation for the reduced sensitivity of existing quantitation methods for dsRNA with modified uridines by characterizing the binding affinities of commonly used anti-dsRNA antibodies. Then, a rapid and sensitive biolayer interferometry (BLI) dsRNA detection assay utilizing Flock House Virus (FHV) B2 protein was developed to overcome the challenges in dsRNA detection and the reduced sensitivity. Results: This assay allows the detection of dsRNA with different uridine modifications (ψ, m1ψ, 5 moU) with similar sensitivity as dsRNA without modification. Furthermore, we demonstrated this method can be used to quantify both short and long dsRNA, as well as hairpin-structured dsRNA, providing a more comprehensive detection for dsRNA impurities. Moreover, we applied this assay to monitor dsRNA removal through a purification process. Conclusions: Taken together, this BLI method could enable real-time monitoring of impurities in IVT mRNA production to prevent immunogenicity stemming from dsRNA. Full article
(This article belongs to the Special Issue State-of-Art in mRNA Therapeutics and Gene Delivery)
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22 pages, 4100 KiB  
Article
Nanoparticle-Mediated Therapy with miR-198 Sensitizes Pancreatic Cancer to Gemcitabine Treatment through Downregulation of VCP-Mediated Autophagy
by Christian Marin-Muller, Dali Li, Jian-Ming Lü, Zhengdong Liang, Osvaldo Vega-Martínez, Sue E. Crawford, Mary K. Estes, William E. Fisher, Changyi Chen and Qizhi Yao
Pharmaceutics 2023, 15(8), 2038; https://doi.org/10.3390/pharmaceutics15082038 - 28 Jul 2023
Cited by 2 | Viewed by 1670
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains an extremely aggressive disease characterized by rapidly acquired multi-drug resistance, including to first-line chemotherapeutic agent gemcitabine. Autophagy is a process that is often exploited by cancer and is one of several intrinsic factors associated with resistance to gemcitabine. [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) remains an extremely aggressive disease characterized by rapidly acquired multi-drug resistance, including to first-line chemotherapeutic agent gemcitabine. Autophagy is a process that is often exploited by cancer and is one of several intrinsic factors associated with resistance to gemcitabine. We have previously found that miR-198 acts as a tumor suppressor in PDAC through the targeting of factors including Valosin-containing protein (VCP). VCP has been reported to play an important role in autophagic flux. In this study, we investigated whether the repression of VCP through miR-198 administration disrupts the autophagy process and sensitizes PDAC cells to gemcitabine treatment in vitro. Moreover, we used LGA-PEI (LPNP) nanoparticles to effectively administer miR-198 to tumors in vivo, inducing tumor sensitization to gemcitabine and leading to a significant reduction in tumor burden and metastases and a concomitant downregulation of VCP expression and autophagy maturation. Our results indicate a potential therapeutic strategy for targeting gemcitabine resistant PDAC and establishes the use of LPNPs for effective therapeutic delivery of nucleic acids in vitro and in vivo. Full article
(This article belongs to the Special Issue State-of-Art in mRNA Therapeutics and Gene Delivery)
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15 pages, 41885 KiB  
Article
Crotamine/siRNA Nanocomplexes for Functional Downregulation of Syndecan-1 in Renal Proximal Tubular Epithelial Cells
by Joana D’Arc Campeiro, Wendy A. Dam, Mirian A. F. Hayashi and Jacob van den Born
Pharmaceutics 2023, 15(6), 1576; https://doi.org/10.3390/pharmaceutics15061576 - 23 May 2023
Cited by 1 | Viewed by 1467
Abstract
Proteinuria drives progressive tubulointerstitial fibrosis in native and transplanted kidneys, mainly through the activation of proximal tubular epithelial cells (PTECs). During proteinuria, PTEC syndecan-1 functions as a docking platform for properdin-mediated alternative complement activation. Non-viral gene delivery vectors to target PTEC syndecan-1 could [...] Read more.
Proteinuria drives progressive tubulointerstitial fibrosis in native and transplanted kidneys, mainly through the activation of proximal tubular epithelial cells (PTECs). During proteinuria, PTEC syndecan-1 functions as a docking platform for properdin-mediated alternative complement activation. Non-viral gene delivery vectors to target PTEC syndecan-1 could be useful to slow down alternative complement activation. In this work, we characterize a PTEC-specific non-viral delivery vector composed of the cell-penetrating peptide crotamine complexed with a syndecan-1 targeting siRNA. Cell biological characterization was performed in the human PTEC HK2 cell line, using confocal microscopy, qRT-PCR, and flow cytometry. PTEC targeting in vivo was carried out in healthy mice. Crotamine/siRNA nanocomplexes are positively charged, about 100 nm in size, resistant to nuclease degradation, and showed in vitro and in vivo specificity and internalization into PTECs. The efficient suppression of syndecan-1 expression in PTECs mediated by these nanocomplexes significantly reduced properdin binding (p < 0.001), as well as the subsequent complement activation by the alternative complement pathway (p < 0.001), as observed in either normal or activated tubular conditions. To conclude, crotamine/siRNA-mediated downregulation of PTEC syndecan-1 reduced the activation of the alternative complement pathway. Therefore, we suggest that the present strategy opens new venues for targeted proximal tubular gene therapy in renal diseases. Full article
(This article belongs to the Special Issue State-of-Art in mRNA Therapeutics and Gene Delivery)
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19 pages, 2684 KiB  
Article
Platelet Activation by Antisense Oligonucleotides (ASOs) in the Göttingen Minipig, including an Evaluation of Glycoprotein VI (GPVI) and Platelet Factor 4 (PF4) Ontogeny
by Allan Valenzuela, Miriam Ayuso, Laura Buyssens, Chloé Bars, Chris Van Ginneken, Yann Tessier and Steven Van Cruchten
Pharmaceutics 2023, 15(4), 1112; https://doi.org/10.3390/pharmaceutics15041112 - 31 Mar 2023
Cited by 3 | Viewed by 2366
Abstract
Antisense oligonucleotide (ASO) is a therapeutic modality that enables selective modulation of undruggable protein targets. However, dose- and sequence-dependent platelet count reductions have been reported in nonclinical studies and clinical trials. The adult Göttingen minipig is an acknowledged nonclinical model for ASO safety [...] Read more.
Antisense oligonucleotide (ASO) is a therapeutic modality that enables selective modulation of undruggable protein targets. However, dose- and sequence-dependent platelet count reductions have been reported in nonclinical studies and clinical trials. The adult Göttingen minipig is an acknowledged nonclinical model for ASO safety testing, and the juvenile Göttingen minipig has been recently proposed for the safety testing of pediatric medicines. This study assessed the effects of various ASO sequences and modifications on Göttingen minipig platelets using in vitro platelet activation and aggregometry assays. The underlying mechanism was investigated further to characterize this animal model for ASO safety testing. In addition, the protein abundance of glycoprotein VI (GPVI) and platelet factor 4 (PF4) was investigated in the adult and juvenile minipigs. Our data on direct platelet activation and aggregation by ASOs in adult minipigs are remarkably comparable to human data. Additionally, PS ASOs bind to platelet collagen receptor GPVI and directly activate minipig platelets in vitro, mirroring the findings in human blood samples. This further corroborates the use of the Göttingen minipig for ASO safety testing. Moreover, the differential abundance of GPVI and PF4 in minipigs provides insight into the influence of ontogeny in potential ASO-induced thrombocytopenia in pediatric patients. Full article
(This article belongs to the Special Issue State-of-Art in mRNA Therapeutics and Gene Delivery)
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17 pages, 2181 KiB  
Article
DLin-MC3-Containing mRNA Lipid Nanoparticles Induce an Antibody Th2-Biased Immune Response Polarization in a Delivery Route-Dependent Manner in Mice
by Altan Yavuz, Céline Coiffier, Cynthia Garapon, Serra Gurcan, Claire Monge, Jean-Yves Exposito, Danielle Campiol Arruda and Bernard Verrier
Pharmaceutics 2023, 15(3), 1009; https://doi.org/10.3390/pharmaceutics15031009 - 21 Mar 2023
Cited by 6 | Viewed by 4016
Abstract
mRNA-based vaccines have made a leap forward since the SARS-CoV-2 pandemic and are currently used to develop anti-infectious therapies. If the selection of a delivery system and an optimized mRNA sequence are two key factors to reach in vivo efficacy, the optimal administration [...] Read more.
mRNA-based vaccines have made a leap forward since the SARS-CoV-2 pandemic and are currently used to develop anti-infectious therapies. If the selection of a delivery system and an optimized mRNA sequence are two key factors to reach in vivo efficacy, the optimal administration route for those vaccines remains unclear. We investigated the influence of lipid components and immunization route regarding the intensity and quality of humoral immune responses in mice. The immunogenicity of HIV-p55Gag encoded mRNA encapsulated into D-Lin-MC3-DMA or GenVoy-ionizable lipid-based LNPs was compared after intramuscular or subcutaneous routes. Three sequential mRNA vaccines were administrated followed by a heterologous boost composed of p24-HIV protein antigen. Despite equivalent IgG kinetic profiles of general humoral responses, IgG1/IgG2a ratio analysis showed a Th2/Th1 balance toward a Th1-biased cellular immune response when both LNPs were administrated via the intramuscular route. Surprisingly, a Th2-biased antibody immunity was observed when DLin-containing vaccine was injected subcutaneously. A protein-based vaccine boost appeared to reverse this balance to a cellular-biased response correlated to an increase in antibody avidity. Our finding suggests that the intrinsic adjuvant effect of ionizable lipids appears to be dependent on the delivery route used, which could be relevant to reach potent and long-lasting immunity after mRNA-based immunization. Full article
(This article belongs to the Special Issue State-of-Art in mRNA Therapeutics and Gene Delivery)
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23 pages, 30873 KiB  
Article
Autologous Genetically Enriched Leucoconcentrate in the Preventive and Acute Phases of Stroke Treatment in a Mini-Pig Model
by Zufar Safiullov, Andrei Izmailov, Mikhail Sokolov, Vage Markosyan, Grayr Kundakchan, Ravil Garifulin, Maksim Shmarov, Boris Naroditsky, Denis Logunov and Rustem Islamov
Pharmaceutics 2022, 14(10), 2209; https://doi.org/10.3390/pharmaceutics14102209 - 17 Oct 2022
Cited by 4 | Viewed by 2025
Abstract
The natural limitations of regeneration in the CNS are major problems for the treatment of neurological disorders, including ischaemic brain strokes. Among the approaches being actively developed to inhibit post-ischaemic negative consequences is the delivery of therapeutic genes encoding neuroprotective molecules to the [...] Read more.
The natural limitations of regeneration in the CNS are major problems for the treatment of neurological disorders, including ischaemic brain strokes. Among the approaches being actively developed to inhibit post-ischaemic negative consequences is the delivery of therapeutic genes encoding neuroprotective molecules to the brain. Unfortunately, there are currently no proven and available medicines that contain recombinant human genes for the treatment of ischaemic cerebral stroke. Of particular interest is the development of treatments for patients at risk of ischaemic stroke. In the present study, we propose a proof of concept for the use of an autologous, genetically enriched leucoconcentrate temporally secreting recombinant vascular endothelial growth factor (VEGF), glial-cell-line-derived neurotrophic factor (GDNF) and the neural cell adhesion molecule (NCAM) for the treatment of stroke. In a mini-pig ischaemic stroke model, genetically enriched leucoconcentrate was infused 4 h after surgery (gene therapy in acute phase) or 2 days before stroke modelling (preventive gene therapy). On day 21, after the stroke modelling, the post-ischaemic brain recovery was examined by morphologic and immunofluorescence analysis. The benefits of treating a stroke with genetically enriched leucoconcentrate both for preventive purposes and in the acute phase were confirmed by an improved performance in behavioural tests, higher preservation of brain tissue and positive post-ischaemic brain remodelling in the peri-infarct area. These results suggest that the employment of autologous leucocytes enabling the temporary production of the recombinant therapeutic molecules to correct the pathological process in the CNS may be one of the breakthrough approaches in gene therapy. Full article
(This article belongs to the Special Issue State-of-Art in mRNA Therapeutics and Gene Delivery)
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