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Pharmaceutics
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mRNA-Based Protein Replacement Therapy
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mRNA-Based Protein Replacement Therapy

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 November 2022) | Viewed by 23296

Special Issue Editor

Dr. Ioannis S. Vizirianakis

E-Mail Website
Guest Editor
Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
Interests: molecular pharmacology; pharmacogenomics; personalized medicine; drug delivery; innovative therapeutics

Special Issue Information

Dear Colleagues,

The way by which the genetic information bearing by mRNAs is translated in ribosomes contributes to molecular mechanisms that support the cellular decisions for the entire lifetime of the organisms. mRNA is the central molecule essential to all forms of life that lies between the “keeper” of the genetic information DNA and the “executor” of the cell structure and function protein. The initial mRNA therapeutic potential was shown about three decades ago, however, through the successful mRNA-based vaccination in COVID-19 pandemic, society’s attention to the mRNA’s therapeutic capacity to deliver genetic information exploitable by the clinical setting has been tremendously revived. The successful confrontation of limiting factors for the broad use of mRNA therapeutics referring to instability, immunogenicity, and limited capacity for cellular delivery have expanded their pharmacological and clinical application repertoire. To this end, nowadays research efforts are focusing on further exploitation of mRNA-based therapeutics to achieve major healthcare benefits by developing cancer vaccines, tumor immunotherapy, protein replacement, and gene editing protocols.

In this Special Issue, we welcome articles dealing with all aspects of mRNA-based protein replacement therapy to combat illnesses, including multi-genic- and multi-factorial—like metabolic and cardiovascular disorders, as well as infectious disease prevention. Researchers are invited to publish their original research, or review articles with expert opinions and perspectives on experimental approaches covering methodologies that can lead to the improvement of crucial preclinical and clinical parameters for mRNA-based therapeutic molecules from bench to bed. Additionally, protocols and approaches with supporting data that improve physicochemical properties, cellular behavior, function, and translation rate, as well as providing evidence of biodistribution, pharmacokinetics, and clinical effectiveness of mRNA-based replacement therapy platforms are also invited for submission and publication. Moreover, we welcome work dealing with the development and application of safe and effective in vivo delivery systems for mRNA therapeutics, including those with targeting propensity of particular cells or organs in the body.

Dr. Ioannis S. Vizirianakis
Guest Editor

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Published Papers (5 papers)

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Research

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21 pages, 5509 KiB  
Article
Safe and Effective Delivery of mRNA Using Modified PEI-Based Lipopolymers
by Huijing Wang, Xin Liu, Xuefeng Ai, K. C. Remant-Bahadur, Teo A. Dick, Bingqian Yan, Tingting Lu, Xingliang Zhou, Runjiao Luo, Minglu Liu, Xiangying Wang, Kaixiang Li, Wei Wang, Hasan Uludag and Wei Fu
Pharmaceutics 2023, 15(2), 410; https://doi.org/10.3390/pharmaceutics15020410 - 26 Jan 2023
Cited by 7 | Viewed by 3498
Abstract
Chemically modified mRNA (modRNA) has proven to be a versatile tool for the treatment of various cancers and infectious diseases due to recent technological advancements. However, a safe and effective delivery system to overcome the complex extracellular and intracellular barriers is required in [...] Read more.
Chemically modified mRNA (modRNA) has proven to be a versatile tool for the treatment of various cancers and infectious diseases due to recent technological advancements. However, a safe and effective delivery system to overcome the complex extracellular and intracellular barriers is required in order to achieve higher therapeutic efficacy and broaden clinical applications. Here, we explored All-Fect and Leu-Fect C as novel transfection reagents derived from lipopolymers, which demonstrated excellent biocompatibility, efficient delivery capabilities, and a robust ability to escape the lysosomes. These properties directly increase mRNA stability by preventing mRNA degradation by nucleases and simultaneously promote efficient gene translation in vitro and in vivo. The modRNA delivered with lipopolymer vectors sustained effective transfection in mouse hearts following direct intramyocardial injection, as well as in major organs (liver and spleen) after systemic administration. No observable immune reactions or systemic toxicity were detected following the systemic administration of lipopolymer-mRNA complexes to additional solid organs. This study identified commercial reagents for the effective delivery of modRNA and may help facilitate the advancement of gene-based interventions involving the safe and effective delivery of nucleic acid drug substances. Full article
(This article belongs to the Special Issue mRNA-Based Protein Replacement Therapy)
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Review

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16 pages, 3220 KiB  
Review
Nanobiotechnology-Enabled mRNA Stabilization
by He Xian, Yue Zhang, Chengzhong Yu and Yue Wang
Pharmaceutics 2023, 15(2), 620; https://doi.org/10.3390/pharmaceutics15020620 - 12 Feb 2023
Cited by 7 | Viewed by 3153
Abstract
mRNA technology has attracted enormous interest due to its great therapeutic potential. Strategies that can stabilize fragile mRNA molecules are crucial for their widespread applications. There are numerous reviews on mRNA delivery, but few focus on the underlying causes of mRNA instability and [...] Read more.
mRNA technology has attracted enormous interest due to its great therapeutic potential. Strategies that can stabilize fragile mRNA molecules are crucial for their widespread applications. There are numerous reviews on mRNA delivery, but few focus on the underlying causes of mRNA instability and how to tackle the instability issues. Herein, the recent progress in nanobiotechnology-enabled strategies for stabilizing mRNA and better delivery is reviewed. First, factors that destabilize mRNA are introduced. Second, nanobiotechnology-enabled strategies to stabilize mRNA molecules are reviewed, including molecular and nanotechnology approaches. The impact of formulation processing on mRNA stability and shelf-life, including freezing and lyophilization, are also briefly discussed. Lastly, our perspectives on challenges and future directions are presented. This review may provide useful guidelines for understanding the structure–function relationship and the rational design of nanobiotechnology for mRNA stability enhancement and mRNA technology development. Full article
(This article belongs to the Special Issue mRNA-Based Protein Replacement Therapy)
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38 pages, 802 KiB  
Review
Protein Transduction Domain-Mediated Delivery of Recombinant Proteins and In Vitro Transcribed mRNAs for Protein Replacement Therapy of Human Severe Genetic Mitochondrial Disorders: The Case of Sco2 Deficiency
by Androulla N. Miliotou, Parthena F. Foltopoulou, Alexandra Ingendoh-Tsakmakidis, Asterios S. Tsiftsoglou, Ioannis S. Vizirianakis, Ioannis S. Pappas and Lefkothea C. Papadopoulou
Pharmaceutics 2023, 15(1), 286; https://doi.org/10.3390/pharmaceutics15010286 - 14 Jan 2023
Cited by 3 | Viewed by 4070
Abstract
Mitochondrial disorders represent a heterogeneous group of genetic disorders with variations in severity and clinical outcomes, mostly characterized by respiratory chain dysfunction and abnormal mitochondrial function. More specifically, mutations in the human SCO2 gene, encoding the mitochondrial inner membrane Sco2 cytochrome c oxidase [...] Read more.
Mitochondrial disorders represent a heterogeneous group of genetic disorders with variations in severity and clinical outcomes, mostly characterized by respiratory chain dysfunction and abnormal mitochondrial function. More specifically, mutations in the human SCO2 gene, encoding the mitochondrial inner membrane Sco2 cytochrome c oxidase (COX) assembly protein, have been implicated in the mitochondrial disorder fatal infantile cardioencephalomyopathy with COX deficiency. Since an effective treatment is still missing, a protein replacement therapy (PRT) was explored using protein transduction domain (PTD) technology. Therefore, the human recombinant full-length mitochondrial protein Sco2, fused to TAT peptide (a common PTD), was produced (fusion Sco2 protein) and successfully transduced into fibroblasts derived from a SCO2/COX-deficient patient. This PRT contributed to effective COX assembly and partial recovery of COX activity. In mice, radiolabeled fusion Sco2 protein was biodistributed in the peripheral tissues of mice and successfully delivered into their mitochondria. Complementary to that, an mRNA-based therapeutic approach has been more recently considered as an innovative treatment option. In particular, a patented, novel PTD-mediated IVT-mRNA delivery platform was developed and applied in recent research efforts. PTD-IVT-mRNA of full-length SCO2 was successfully transduced into the fibroblasts derived from a SCO2/COX-deficient patient, translated in host ribosomes into a nascent chain of human Sco2, imported into mitochondria, and processed to the mature protein. Consequently, the recovery of reduced COX activity was achieved, thus suggesting the potential of this mRNA-based technology for clinical translation as a PRT for metabolic/genetic disorders. In this review, such research efforts will be comprehensibly presented and discussed to elaborate their potential in clinical application and therapeutic usefulness. Full article
(This article belongs to the Special Issue mRNA-Based Protein Replacement Therapy)
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10 pages, 876 KiB  
Review
What Can RNA-Based Therapy Do for Monogenic Diseases?
by Luka A. Clarke and Margarida D. Amaral
Pharmaceutics 2023, 15(1), 260; https://doi.org/10.3390/pharmaceutics15010260 - 12 Jan 2023
Cited by 2 | Viewed by 3279
Abstract
The use of RNA-based approaches to treat monogenic diseases (i.e., hereditary disorders caused by mutations in single genes) has been developed on different fronts. One approach uses small antisense oligonucleotides (ASOs) to modulate RNA processing at various stages; namely, to enhance correct splicing, [...] Read more.
The use of RNA-based approaches to treat monogenic diseases (i.e., hereditary disorders caused by mutations in single genes) has been developed on different fronts. One approach uses small antisense oligonucleotides (ASOs) to modulate RNA processing at various stages; namely, to enhance correct splicing, to stimulate exon skipping (to exclude premature termination codon variants), to avoid undesired messenger RNA (mRNA) transcript degradation via the nonsense-mediated decay (NMD) pathway, or to induce mRNA degradation where they encode toxic proteins (e.g., in dominant diseases). Another approach consists in administering mRNA, which, like gene therapy, is a mutation-agnostic approach with potential application to any recessive monogenic disease. This is simpler than gene therapy because instead of requiring targeting of the nucleus, the mRNA only needs to be delivered to the cytoplasm. Although very promising (as demonstrated by COVID-19 vaccines), these approaches still have potential for optimisation, namely regarding delivery efficiency, adverse drug reactions and toxicity. Full article
(This article belongs to the Special Issue mRNA-Based Protein Replacement Therapy)
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19 pages, 2506 KiB  
Review
mRNA in the Context of Protein Replacement Therapy
by Theofanis Vavilis, Eleni Stamoula, Alexandra Ainatzoglou, Athanasios Sachinidis, Malamatenia Lamprinou, Ioannis Dardalas and Ioannis S. Vizirianakis
Pharmaceutics 2023, 15(1), 166; https://doi.org/10.3390/pharmaceutics15010166 - 3 Jan 2023
Cited by 40 | Viewed by 7892
Abstract
Protein replacement therapy is an umbrella term used for medical treatments that aim to substitute or replenish specific protein deficiencies that result either from the protein being absent or non-functional due to mutations in affected patients. Traditionally, such an approach requires a well [...] Read more.
Protein replacement therapy is an umbrella term used for medical treatments that aim to substitute or replenish specific protein deficiencies that result either from the protein being absent or non-functional due to mutations in affected patients. Traditionally, such an approach requires a well characterized but arduous and expensive protein production procedure that employs in vitro expression and translation of the pharmaceutical protein in host cells, followed by extensive purification steps. In the wake of the SARS-CoV-2 pandemic, mRNA-based pharmaceuticals were recruited to achieve rapid in vivo production of antigens, proving that the in vivo translation of exogenously administered mRNA is nowadays a viable therapeutic option. In addition, the urgency of the situation and worldwide demand for mRNA-based medicine has led to an evolution in relevant technologies, such as in vitro transcription and nanolipid carriers. In this review, we present preclinical and clinical applications of mRNA as a tool for protein replacement therapy, alongside with information pertaining to the manufacture of modified mRNA through in vitro transcription, carriers employed for its intracellular delivery and critical quality attributes pertaining to the finished product. Full article
(This article belongs to the Special Issue mRNA-Based Protein Replacement Therapy)
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