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1.
J Phys Chem Lett ; 13(5): 1314-1322, 2022 Feb 10.
Article in English | MEDLINE | ID: covidwho-1671478

ABSTRACT

With the global outbreak of SARS-CoV-2, mRNA vaccines became the first type of COVID-19 vaccines to enter clinical trials because of their facile production, low cost, and relative safety, which initiated great advances in mRNA therapeutic techniques. However, the development of mRNA therapeutic techniques still confronts some challenges. First, in vitro transcribed mRNA molecules can be easily degraded by ribonuclease (RNase), resulting in their low stability. Next, the negative charge of mRNA molecules prevents them from direct cell entry. Therefore, finding efficient and safe delivery technology could be the key issue to improve mRNA therapeutic techniques. In this Perspective, we mainly discuss the problems of the existing mRNA-based delivery nanoplatforms, including safety evaluation, administration routes, and preparation technology. Moreover, we also propose some views on strategies to further improve mRNA delivery technology.


Subject(s)
COVID-19 Vaccines/administration & dosage , RNA, Messenger/administration & dosage , Vaccines, Synthetic/administration & dosage , /administration & dosage , Drug Stability , Drug Storage , High-Throughput Screening Assays , Humans
2.
Chem Phys Lipids ; 243: 105178, 2022 03.
Article in English | MEDLINE | ID: covidwho-1664753

ABSTRACT

Lipid nanoparticles (LNPs) mediated mRNA delivery has gained prominence due to the success of mRNA vaccines against Covid-19, without which it would not have been possible. However, there is little clinical validation of this technology for other mRNA-based therapeutic approaches. Systemic administration of LNPs predominantly targets the liver, but delivery to other organs remains a challenge. Local approaches remain a viable option for some disease indications, such as Cystic Fibrosis, where aerosolized delivery to airway epithelium is the preferred route of administration. With this in mind, novel cationic lipids (L1-L4) have been designed, synthesized and co-formulated with a proprietary ionizable lipid. These LNPs were further nebulized, along with baseline control DOTAP-based LNP (DOTAP+), and tested in vitro for mRNA integrity and encapsulation efficiency, as well as transfection efficiency and cytotoxicity in cell cultures. Improved biodegradability and potentially superior elimination profiles of L1-L4, in part due to physicochemical characteristics of putative metabolites, are thought to be advantageous for prospective therapeutic lung delivery applications using these lipids.


Subject(s)
Liposomes/chemistry , Lung , Nanoparticles/chemistry , RNA, Messenger/administration & dosage , Humans
5.
Biomed Pharmacother ; 145: 112385, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1565522

ABSTRACT

Chemically modified mRNA represents a unique, efficient, and straightforward approach to produce a class of biopharmaceutical agents. It has been already approved as a vaccination-based method for targeting SARS-CoV-2 virus. The COVID-19 pandemic has highlighted the prospect of synthetic modified mRNA to efficiently and safely combat various diseases. Recently, various optimization advances have been adopted to overcome the limitations associated with conventional gene therapeutics leading to wide-ranging applications in different disease conditions. This review sheds light on emerging directions of chemically modified mRNAs to prevent and treat widespread chronic diseases, including metabolic disorders, cancer vaccination and immunotherapy, musculoskeletal disorders, respiratory conditions, cardiovascular diseases, and liver diseases.


Subject(s)
COVID-19/prevention & control , Chronic Disease/prevention & control , Chronic Disease/therapy , Genetic Therapy/methods , Immunotherapy/methods , Pandemics/prevention & control , RNA, Messenger/chemistry , SARS-CoV-2/immunology , Vaccines, Synthetic , Biological Availability , Drug Carriers , Forecasting , Gene Transfer Techniques , Genetic Vectors/administration & dosage , Genetic Vectors/therapeutic use , Humans , Immunotherapy, Active , RNA Stability , RNA, Messenger/administration & dosage , RNA, Messenger/immunology , RNA, Messenger/therapeutic use , SARS-CoV-2/genetics , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/immunology , /immunology
7.
Adv Drug Deliv Rev ; 179: 114007, 2021 12.
Article in English | MEDLINE | ID: covidwho-1482395

ABSTRACT

In recent years, nucleic acid-based therapeutics have gained increasing importance as novel treatment options for disease prevention and treatment. Synthetic messenger RNAs (mRNAs) are promising nucleic acid-based drugs to transiently express desired proteins that are missing or defective. Recently, synthetic mRNA-based vaccines encoding viral proteins have been approved for emergency use against COVID-19. Various types of vehicles, such as lipid nanoparticles (LNPs) and liposomes, are being investigated to enable the efficient uptake of mRNA molecules into desired cells. In addition, the introduction of novel chemical modifications into mRNAs increased the stability, enabled the modulation of nucleic acid-based drugs, and increased the efficiency of mRNA-based therapeutic approaches. In this review, novel and innovative strategies for the delivery of synthetic mRNA-based therapeutics for tissue regeneration are discussed. Moreover, with this review, we aim to highlight the versatility of synthetic mRNA molecules for various applications in the field of regenerative medicine and also discuss translational challenges and required improvements for mRNA-based drugs.


Subject(s)
Drug Delivery Systems , RNA, Messenger/administration & dosage , Regeneration , Regenerative Medicine/trends , Animals , COVID-19 Vaccines/administration & dosage , Gene Transfer Techniques , Genetic Therapy , Humans , RNA, Messenger/immunology
8.
Adv Drug Deliv Rev ; 177: 113930, 2021 10.
Article in English | MEDLINE | ID: covidwho-1355525

ABSTRACT

Messenger RNAs (mRNAs) present a great potential as therapeutics for the treatment and prevention of a wide range of human pathologies, allowing for protein replacement, vaccination, cancer immunotherapy, and genomic engineering. Despite advances in the design of mRNA-based therapeutics, a key aspect for their widespread translation to clinic is the development of safe and effective delivery strategies. To this end, non-viral delivery systems including peptide-based complexes, lipidic or polymeric nanoparticles, and hybrid formulations are attracting growing interest. Despite displaying somewhat reduced efficacy compared to viral-based systems, non-viral carriers offer important advantages in terms of biosafety and versatility. In this review, we provide an overview of current mRNA therapeutic applications and discuss key biological barriers to delivery and recent advances in the development of non-viral systems. Challenges and future applications of this novel therapeutic modality are also discussed.


Subject(s)
RNA, Messenger/administration & dosage , Animals , Drug Delivery Systems , Gene Transfer Techniques , Humans
9.
Cell ; 184(21): 5271-5274, 2021 10 14.
Article in English | MEDLINE | ID: covidwho-1433036

ABSTRACT

This year's Lasker∼Debakey Clinical Research Award honors Katalin Karikó and Drew Weissman for the development of a therapeutic technology based on nucleoside-modification of messenger RNA, enabling the rapid development of the highly effective COVID-19 vaccines.


Subject(s)
Biotechnology/methods , COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , RNA, Messenger/administration & dosage , SARS-CoV-2/immunology , Vaccines, Synthetic/administration & dosage , COVID-19/epidemiology , COVID-19/immunology , COVID-19/virology , Humans , RNA, Messenger/chemistry
10.
Cell ; 184(21): 5293-5296, 2021 10 14.
Article in English | MEDLINE | ID: covidwho-1433035

ABSTRACT

The highly effective and safe mRNA-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines draw on decades of painstaking research to overcome the many hurdles for delivering, expressing, and avoiding toxicity of therapeutic mRNA. Cell editor Nicole Neuman talked with Dr. Katalin Karikó and Dr. Drew Weissman, recipients of the 2021 Lasker∼DeBakey Clinical Medical Research Award, to learn more about their quest to develop mRNA-based therapeutics, which led them to the crucial discovery that modification of mRNA could prevent toxicity and increase expression. This conversation has been adapted for print below, with editing for clarity, accuracy, and length.


Subject(s)
Biotechnology/methods , COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , RNA, Messenger/administration & dosage , SARS-CoV-2/immunology , Vaccines, Synthetic/administration & dosage , COVID-19/epidemiology , COVID-19/immunology , COVID-19/virology , Drug Discovery , Humans , Interviews as Topic , RNA, Messenger/chemistry
11.
Adv Drug Deliv Rev ; 176: 113900, 2021 09.
Article in English | MEDLINE | ID: covidwho-1384817

ABSTRACT

The recent approval of messenger RNA (mRNA)-based vaccines to combat the SARS-CoV-2 pandemic highlights the potential of both conventional mRNA and self-amplifying mRNA (saRNA) as a flexible immunotherapy platform to treat infectious diseases. Besides the antigen it encodes, mRNA itself has an immune-stimulating activity that can contribute to vaccine efficacy. This self-adjuvant effect, however, will interfere with mRNA translation and may influence the desired therapeutic outcome. To further exploit its potential as a versatile therapeutic platform, it will be crucial to control mRNA's innate immune-stimulating properties. In this regard, we describe the mechanisms behind the innate immune recognition of mRNA and provide an extensive overview of strategies to control its innate immune-stimulating activity. These strategies range from modifications to the mRNA backbone itself, optimization of production and purification processes to the combination with innate immune inhibitors. Furthermore, we discuss the delicate balance of the self-adjuvant effect in mRNA vaccination strategies, which can be both beneficial and detrimental to the therapeutic outcome.


Subject(s)
Gene Amplification/immunology , Immunity, Innate/immunology , Immunotherapy/methods , RNA, Messenger/immunology , Vaccines, Synthetic/immunology , Animals , COVID-19/genetics , COVID-19/immunology , COVID-19/prevention & control , Gene Amplification/drug effects , Humans , Immunity, Innate/drug effects , Immunotherapy/trends , RNA, Messenger/administration & dosage , RNA, Messenger/genetics , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/genetics
13.
Commun Biol ; 4(1): 956, 2021 08 11.
Article in English | MEDLINE | ID: covidwho-1354120

ABSTRACT

Lipid Nanoparticles (LNPs) are used to deliver siRNA and COVID-19 mRNA vaccines. The main factor known to determine their delivery efficiency is the pKa of the LNP containing an ionizable lipid. Herein, we report a method that can predict the LNP pKa from the structure of the ionizable lipid. We used theoretical, NMR, fluorescent-dye binding, and electrophoretic mobility methods to comprehensively measure protonation of both the ionizable lipid and the formulated LNP. The pKa of the ionizable lipid was 2-3 units higher than the pKa of the LNP primarily due to proton solvation energy differences between the LNP and aqueous medium. We exploited these results to explain a wide range of delivery efficiencies in vitro and in vivo for intramuscular (IM) and intravascular (IV) administration of different ionizable lipids at escalating ionizable lipid-to-mRNA ratios in the LNP. In addition, we determined that more negatively charged LNPs exhibit higher off-target systemic expression of mRNA in the liver following IM administration. This undesirable systemic off-target expression of mRNA-LNP vaccines could be minimized through appropriate design of the ionizable lipid and LNP.


Subject(s)
Gene Expression , Ions/chemistry , Lipids/chemistry , Nanoparticles/chemistry , RNA, Messenger/chemistry , RNA, Messenger/genetics , Administration, Intravenous , Animals , Drug Compounding , Humans , Hydrogen-Ion Concentration , Injections, Intramuscular , Mice , Molecular Structure , Nanoparticles/ultrastructure , RNA, Messenger/administration & dosage , RNA, Messenger/pharmacokinetics , Spectrum Analysis , Tissue Distribution , Transfection
15.
J Immunother Cancer ; 9(6)2021 06.
Article in English | MEDLINE | ID: covidwho-1266401

ABSTRACT

SARS-CoV-2 infection and the resulting COVID-19 have afflicted millions of people in an ongoing worldwide pandemic. Safe and effective vaccination is needed urgently to protect not only the general population but also vulnerable subjects such as patients with cancer. Currently approved mRNA-based SARS-CoV-2 vaccines seem suitable for patients with cancer based on their mode of action, efficacy, and favorable safety profile reported in the general population. Here, we provide an overview of mRNA-based vaccines including their safety and efficacy. Extrapolating from insights gained from a different preventable viral infection, we review existing data on immunity against influenza A and B vaccines in patients with cancer. Finally, we discuss COVID-19 vaccination in light of the challenges specific to patients with cancer, such as factors that may hinder protective SARS-CoV-2 immune responses in the context of compromised immunity and the use of immune-suppressive or immune-modulating drugs.


Subject(s)
COVID-19 Vaccines , Neoplasms/therapy , RNA, Messenger , SARS-CoV-2/immunology , Viral Vaccines , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines/genetics , COVID-19 Vaccines/therapeutic use , Drug Stability , Humans , Influenza, Human/epidemiology , Influenza, Human/immunology , Influenza, Human/prevention & control , Neoplasms/epidemiology , Neoplasms/immunology , Pandemics , RNA Stability/physiology , RNA, Messenger/administration & dosage , RNA, Messenger/adverse effects , RNA, Messenger/chemistry , RNA, Messenger/genetics , SARS-CoV-2/genetics , Vaccination/methods , Viral Vaccines/adverse effects , Viral Vaccines/chemistry , Viral Vaccines/genetics
16.
Sci Rep ; 11(1): 371, 2021 01 11.
Article in English | MEDLINE | ID: covidwho-1242035

ABSTRACT

Vaccines and therapeutics using in vitro transcribed mRNA hold enormous potential for human and veterinary medicine. Transfection agents are widely considered to be necessary to protect mRNA and enhance transfection, but they add expense and raise concerns regarding quality control and safety. We found that such complex mRNA delivery systems can be avoided when transfecting epithelial cells by aerosolizing the mRNA into micron-sized droplets. In an equine in vivo model, we demonstrated that the translation of mRNA into a functional protein did not depend on the addition of a polyethylenimine (PEI)-derived transfection agent. We were able to safely and effectively transfect the bronchial epithelium of foals using naked mRNA (i.e., mRNA formulated in a sodium citrate buffer without a delivery vehicle). Endoscopic examination of the bronchial tree and histology of mucosal biopsies indicated no gross or microscopic adverse effects of the transfection. Our data suggest that mRNA administered by an atomization device eliminates the need for chemical transfection agents, which can reduce the cost and the safety risks of delivering mRNA to the respiratory tract of animals and humans.


Subject(s)
Horses , Nasal Sprays , RNA, Messenger/administration & dosage , Respiratory Mucosa , Animals , Animals, Newborn , Cells, Cultured , Drug Carriers/administration & dosage , Drug Carriers/adverse effects , Drug Carriers/pharmacokinetics , Drug Delivery Systems/adverse effects , Drug Delivery Systems/methods , Drug Delivery Systems/veterinary , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Female , Lung/drug effects , Lung/metabolism , Nebulizers and Vaporizers/veterinary , Polyethyleneimine/administration & dosage , Polyethyleneimine/chemistry , RNA, Messenger/adverse effects , RNA, Messenger/pharmacokinetics , Respiratory Mucosa/drug effects , Respiratory Mucosa/metabolism , Transcription, Genetic , Transfection/methods , Transfection/veterinary , Vaccines, DNA/administration & dosage , Vaccines, DNA/adverse effects , Vaccines, DNA/pharmacokinetics
17.
Curr Opin Virol ; 48: 65-72, 2021 06.
Article in English | MEDLINE | ID: covidwho-1203009

ABSTRACT

Vaccines based on mRNA-containing lipid nanoparticles (LNPs) pioneered by Katalin Karikó and Drew Weissman at the University of Pennsylvania are a promising new vaccine platform used by two of the leading vaccines against coronavirus disease in 2019 (COVID-19). However, there are many questions regarding their mechanism of action in humans that remain unanswered. Here we consider the immunological features of LNP components and off-target effects of the mRNA, both of which could increase the risk of side effects. We suggest ways to mitigate these potential risks by harnessing dendritic cell (DC) biology.


Subject(s)
Dendritic Cells/immunology , Immunization/methods , Lipids , Nanoparticles , RNA, Messenger , Vaccines/classification , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Humans , Lipids/administration & dosage , Lipids/immunology , Nanoparticles/administration & dosage , Nanoparticles/metabolism , RNA, Messenger/administration & dosage , RNA, Messenger/immunology
19.
Clin Chem Lab Med ; 59(9): 1585-1591, 2021 Aug 26.
Article in English | MEDLINE | ID: covidwho-1175447

ABSTRACT

OBJECTIVES: Since universal vaccination is a pillar against coronavirus disease 2019 (COVID-19), monitoring anti-SARS-CoV-2 neutralizing antibodies is essential for deciphering post-vaccination immune response. METHODS: Three healthcare workers received 30 µg BNT162b2 mRNA Covid-19 Pfizer Vaccine, followed by a second identical dose, 21 days afterwards. Venous blood was drawn at baseline and at serial intervals, up to 63 days afterwards, for assessing total immunoglobulins (Ig) anti-RBD (receptor binding domain), anti-S1/S2 and anti-RBD IgG, anti-RBD and anti-N/S1 IgM, and anti-S1 IgA. RESULTS: All subjects were SARS-CoV-2 seronegative at baseline. Total Ig anti-RBD, anti-S1/S2 and anti-RBD IgG levels increased between 91 and 368 folds until 21 days after the first vaccine dose, then reached a plateau. The levels raised further after the second dose (by ∼30-, ∼8- and ∼8-fold, respectively), peaking at day 35, but then slightly declining and stabilizing ∼50 days after the first vaccine dose. Anti-S1 IgA levels increased between 7 and 11 days after the first dose, slightly declined before the second dose, after which levels augmented by ∼24-fold from baseline. The anti-RBD and anti-N/S1 IgM kinetics were similar to that of anti-S1 IgA, though displaying substantially weaker increases and modest peaks, only 4- to 7-fold higher than baseline. Highly significant inter-correlation was noted between total Ig anti-RBD, anti-S1/S2 and anti-RBD IgG (all r=0.99), whilst other anti-SARS-CoV-2 antibodies displayed lower, though still significant, correlations. Serum spike protein concentration was undetectable at all-time points. CONCLUSIONS: BNT162b2 mRNA vaccination generates a robust humoral immune response, especially involving anti-SARS-Cov-2 IgG and IgA, magnified by the second vaccine dose.


Subject(s)
Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , Immunity/immunology , RNA, Messenger/immunology , SARS-CoV-2/immunology , Vaccination/methods , Adult , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/genetics , Female , Humans , Male , Middle Aged , RNA, Messenger/administration & dosage , RNA, Messenger/genetics , SARS-CoV-2/genetics
20.
Viruses ; 13(3)2021 03 05.
Article in English | MEDLINE | ID: covidwho-1167750

ABSTRACT

Although antibody levels progressively decrease following SARS-CoV-2 infection, the immune memory persists for months. Thus, individuals who naturally contracted SARS-CoV-2 are expected to develop a more rapid and sustained response to COVID-19 vaccines than naïve individuals. In this study, we analyzed the dynamics of the antibody response to the BNT162b2 mRNA COVID-19 vaccine in six healthcare workers who contracted SARS-CoV-2 in March 2020, in comparison to nine control subjects without a previous infection. The vaccine was well tolerated by both groups, with no significant difference in the frequency of vaccine-associated side effects, with the exception of local pain, which was more common in previously infected subjects. Overall, the titers of neutralizing antibodies were markedly higher in response to the vaccine than after natural infection. In all subjects with pre-existing immunity, a rapid increase in anti-spike receptor-binding domain (RBD) IgG antibodies and neutralizing antibody titers was observed one week after the first dose, which seemed to act as a booster. Notably, in previously infected individuals, neutralizing antibody titers 7 days after the first vaccine dose were not significantly different from those observed in naïve subjects 7 days after the second vaccine dose. These results suggest that, in previously infected people, a single dose of the vaccine might be sufficient to induce an effective response.


Subject(s)
Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , RNA, Messenger/immunology , RNA, Viral/immunology , SARS-CoV-2/immunology , Adult , Antibody Formation , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/genetics , Female , Humans , Immunoglobulin G/immunology , Male , Middle Aged , RNA, Messenger/administration & dosage , RNA, Messenger/genetics , RNA, Viral/administration & dosage , RNA, Viral/genetics , SARS-CoV-2/genetics
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