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Updated: Jul 14

Technical Review Article | Open Access | Published 11th July 2025

Development Of mRNA Vaccines And Therapeutics Beyond Covid-19


Anubhi Yadav, Akanksha Dwivedi,*, G. N. Darwhekar , Acropolis Institute of Pharmaceutical Education and Research, Indore EJPPS | 302 (2025) | https://doi.org/10.37521/ejpps30211

Abstract 


A new era in medicine has been made possible by recent developments in mRNA technology as well as its delivery. Since mRNA-encoded proteins don't have to plunge into the nucleus or be exposed to the possibility of integrating genetically, they are quick, powerful, and temporary, which makes them ideal for treating various types of illnesses, including cancer, contagious illnesses and monogenic disorders.

The worldwide reaction to the COVID-19 pandemic was aided by the quick turnaround time and simplicity of mass-scale manufacturing of mRNA-based treatments. However, issues with mRNA stability, expression length, delivery effectiveness, and targetability all need to be resolved in order to expand the use of mRNA therapies beyond COVID-19 vaccinations.

We are able to optimize the platform of mRNA to satisfy the clinical prerequisites for any illness by taking lessons from the quickly growing preclinical and clinical research. In order to create a new generation of targeted mRNA-dependent treatments, we will anticipate an overview of the latest developments in mRNA technology, including its application in vaccines, immunotherapeutic, protein replacement therapy, and genome editing as well as its distribution to particular cell types and organs.


Keywords: mRNA vaccines, preclinical trials, clinical trials, immunogenicity, tumour, antibodies, safety, efficacy, pharmacokinetic studies, immune responses, genomic editing, therapeutic uses.


Introduction


RNA-based medications have drawn a lot of attention, primarily due to the effective development of mRNA vaccines to combat the COVID-19 pandemic.¹,²,³ mRNA is a molecule that can be transformed into target proteins once it enters into the cells.⁴,⁵ In order to treat disorders for which the expression of particular therapeutic protein types is necessary, mRNA can be used to create therapeutic substances. mRNA’s translation efficiency is higher and can cause temporary protein expression as compared to DNA, another form of nucleic acid that can produce encoded proteins in cells. But there were a number of obstacles to overcome before mRNA could be used therapeutically. First, mRNA structures break down easily in serum.

Therefore, methods for delivering and safeguarding mRNA into specific cells were needed. Lipid nanoparticles (LNP), liposomes, cationic polymers and inorganic nanoparticles are among the different kinds of biomaterials that have been created as mRNA transport materials for this purpose.⁶ Second, when mRNA enters cells, it might trigger innate immune responses because it is identified by different pattern recognition receptors (PRRs).⁷ The therapeutic uses of mRNA may be limited since the immunological responses that mRNAs elicit may have detrimental impacts on the therapy of disease.

In the meantime, our bodies must express target antigens and trigger immune responses in order to create vaccines that work. mRNA can meet the conditions for effective vaccinations since it can concurrently stimulate translation and immune activation. According to this perspective, mRNA has been considered a promising new vaccination platform. Until now, mRNA-based medications have mostly been used in clinical settings to create vaccines, either for infectious disease prevention or cancer immunotherapy.⁵ Apart from its application in the creation of vaccines, mRNA has recently demonstrated encouraging outcomes in the management of a number of illnesses. Protein replacement therapy, which uses mRNA to create therapeutic proteins that are therapeutically available, and innovative therapeutic approaches such as gene editing and ex vivo/in vivo cell engineering are some examples of these applications.⁸,⁹,¹⁰

The quick creation of mRNA vaccines has helped control the recent COVID-19 outbreak, indicating that the described technology could be utilised to control infectious disease pandemics in the future. Particularly in the midst of fast-spreading infectious disease outbreaks, mRNA vaccines are ideal for development because the antigens they target may be readily modified by merely altering the pattern found within the mRNA structure coding regions. mRNA vaccines have the ability to successfully induce antigen-specific immune responses by exhibiting target antigens in cells and concurrently eliciting immunological responses, in addition to enabling rapid development. In fact, the U.S. Food and Drug Administration has authorized two COVID-19 mRNA vaccines, both of which have demonstrated a high level of effectiveness in preventing infections. Options for treating disorders that are difficult to treat have been made possible by mRNA's capacity to make target proteins that are faulty in particular conditions.

Safe delivery of mRNA molecules into specified cells is necessary for clinical applications of mRNA vaccines and therapies. The information currently available regarding mRNA vaccines and treatments, their clinical uses, and their delivery methods is compiled in this review. In clinical settings where the production of particular proteins is necessary, mRNA can be used. Additionally, by triggering immunological responses and antigen expression, mRNA can be used to create a vaccine. For mRNA-based medicines and vaccines to be used therapeutically, delivery methods are necessary. mRNA-based medications and their delivery methods will be covered in this review.


mRNA VACCINES

By infecting antigen-presenting cells with synthesized mRNA that encodes pathogen antigens, mRNA vaccines elicit immune responses (Figure 1). Immune cells process, present, or produce these particular antigens on the surface of the cell and immune cells recognize them, leading to cytotoxic and protective humoral T-cell responses. The preclinical research and clinical outcomes of coronavirus vaccinations and products have been the subject of several studies and research publications.¹¹⁻¹⁶

Despite the fact that mRNA vaccinations have demonstrated efficacy in protecting in opposition to infectious diseases, there are still issues to be resolved. These issues include increasing immunologic reactivity, as methods to elicit more powerful immune reactions, for example optimising dosages, distribution methods, and auxiliaries, are investigated; producing customised mRNA vaccines, as customising vaccinations to each person’s immunological profile may boost efficacy and lower risk; and focusing on adverse effects, as initiatives to minimise side effects while preserving vaccine’s efficacy as an essential aspect.

In general, even though mRNA vaccinations have already demonstrated a lot of promise, further investigation and advancement are necessary to overcome obstacles and enhance their safety, efficacy, and resilience.


Figure 1: The method by which immunity is generated by mRNA vaccines. Lipid nanoparticles containing synthetic mRNA encoding the antigen are delivered for absorption by antigen-presenting cells. In order to combat the infection, humoral antibodies and cytotoxic T-cell reactions are produced as part of a subsequent immunological response that is adaptive. Additionally, antigen-specific to memory T cells and B cells can possibly be produced, providing defence against infections in the future. Antigen-presenting cells, or APCs. GC stands for germinal centre. Lipid nanoparticles, or LNPs. A major histocompatibility complex is called MHC. Open Reading Frame, or ORF. T-cell receptor, or TCR. Follicle helper T cells are known as Tfh. Untranslated region, or UTR.
Figure 1: The method by which immunity is generated by mRNA vaccines. Lipid nanoparticles containing synthetic mRNA encoding the antigen are delivered for absorption by antigen-presenting cells. In order to combat the infection, humoral antibodies and cytotoxic T-cell reactions are produced as part of a subsequent immunological response that is adaptive. Additionally, antigen-specific to memory T cells and B cells can possibly be produced, providing defence against infections in the future. Antigen-presenting cells, or APCs. GC stands for germinal centre. Lipid nanoparticles, or LNPs. A major histocompatibility complex is called MHC. Open Reading Frame, or ORF. T-cell receptor, or TCR. Follicle helper T cells are known as Tfh. Untranslated region, or UTR.

VACCINES AGAINST INFECTIOUS DISEASES

HIV

HIV still affects 38 million people worldwide even though more than 40 years of investigations have been done, due to the antigenic varieties of the envelope glycoprotein (Env), the thick glycosylation shell that conceals important viral protein epitopes, and also quick alteration of the epitopes. The native Env trimers present on the surface of the virus are architecturally active, continuously changing between three or more conformations, revealing the range in epitopes, according to structural investigations. The duration of the trimer’s transitions between an open stage (tier 1A), an intermediate stage (tier 1B), or a closed stage (tiers 2 and 3) is reflected in the neutralization tier phenotypes.¹⁷ Protection is correlated with neutralizing the viruses of tier 2 and tier 3. Numerous environmental immunogens cause tier 1 neutralization but not tier 2. The goal of developing an HIV-1 vaccine is to produce broad, tier 2 viral strain-neutralizing antibodies.

Preclinical research using prototypic native-like trimer vaccination has demonstrated tier 2 neutralising antibody reactions in rabbits and non-human primates, marking advancements in the possible creation of an HIV-1 vaccine.¹⁸,¹⁹ For at least 41 weeks, non-human primates given an HIV-1 mRNA-LNP vaccination developed long-lasting neutralising antibodies.²⁰ Numerous Phase 1 clinical trials are currently ongoing, highlighting the potential of mRNA for the development of complex HIV-1 vaccine.

Clinical trials investigating the utilisation of broadly neutralising antibodies (bnAbs) focusing on conserved epitopes on the membrane of glycoproteins for therapeutic or preventative approaches are ongoing.²¹A clinical study (NCT03547245) examined the use of a germline-focusing immunogen (eOD-GT8 60mer) to activate uncommon bnAb precursors of B cells that are unique to the specific region of the HIV-1 virus envelope of the protein. Studies have found that healthy persons having median memory B cell with the frequency of 0.1% had VRC01-class responses when given the adjuvant AS01B (monophosphoryl lipid A and saponin).²² The altered mRNA-LNP-encoded antigen (NCT05001373) produced comparable outcomes. In addition to supporting the development of enhanced routines to bring about VRC01-class bnAbs, the results provide clinical demonstration of the concept for germline-target priming and promote the extension of this technique to other targets in HIV and other diseases.²²


Tuberculosis

Mycobacterium tuberculosis is the infectious agent of tuberculosis (TB), a communicable bacterial illness that primarily infects the lungs and can also affect other organs. About 1.4 million fatalities from tuberculosis occur each year, mostly in low-income nations, and the disease is primarily spread by inhaling bacteria from infected individuals.²³ As of now, there isn't a licensed mRNA vaccine for tuberculosis, despite the fact that many vaccines are undergoing clinical trials. The primary licensed tuberculosis vaccine is Bacillus Calmette-Guérin (BCG).²⁴ In 2004, RNA vaccine was used for expressing the Mycobacterium tuberculosis MPT83 antigen. Xue and the colleagues presented the first protective immunisation against bacteria present intracellularly; however, the protection was not as strong as that achieved with BCG. ²⁵,²⁶ BioNTech and the Bill and Melinda Gates Foundation, in 2022, collaborated to launch a Phase 1 clinical trial (NCT05547464) for two potential mRNA vaccines against TB. The trial assessed the vaccine candidates' immunogenicity, protection, and reactogenicity in HIV-negative, BCG-vaccinated subjects. The safety of three BNT164 vaccination concentrations is being investigated. It may take years for a new mRNA tuberculosis vaccine to become publicly accessible due to its complicated and difficult development procedure. To prove safety and efficacy in humans, more study is needed.


Influenza virus

New strains of influenza viruses are constantly emerging due to the virus's quick antigenic diversity.²⁷ Types A, B, C, and D are the four major genera. The majority of flu outbreaks are caused by Types A and B, which have a significant negative economic impact and cause 300,000 to 600,000 deaths annually.²⁸ A century ago, the H1N1 influenza A virus caused the first known influenza pandemic, also referred to as the Spanish flu, which brought influenza to the world.²⁹ There have been several pandemics since then. Due to the rapid viral mutation, influenza persists as a global problem despite several preventative vaccinations, requiring regular vaccination improvements for every season of the flu. Because mRNA-LNPs elicit robust immunological reactions and facilitate quick adaptability to novel varieties of antigens, they hold potential for developing effective influenza virus vaccines.

Since 2012, mice, ferrets, and cynomolgus monkeys have demonstrated strong and protective immune responses to influenza viruses H1N1, H10N8, as well as H7N9 that encode fully with haemagglutinin (HA) via mRNA-LNP.³⁰,³¹ An intradermal injection of 10–30 μg of mRNA-LNP (2009 H1N1) produced long-lasting antibodies against the HA stalk, protecting mice against homologous and heterologous influenza challenges, according to Pardi and colleagues.³⁸ Additionally, follicular helper T-cells and germinal centres, activated with HA mRNA-LNP immunization, suggesting extreme quality B-cell results.³⁸,³² Mice which received a combination of multiple antigenic (NA, M2, Stalk, and NP) mRNA-LNP vaccinations showed extensive cross-protection, suggesting a viable strategy for overall influenza vaccination.³³

Uncertainties regarding a particular virus and the animals that harbour it for a future outbreak make it difficult to develop effective pre-pandemic vaccinations. The development of influenza vaccinations that encode HA antigens to every known influenza A and B subtype has been made possible by advances in mRNA-LNP technology. These multivalent vaccines provide protection against deadly influenza infections by eliciting potent cross-reactivity and subtype-specificity in immunological reactions.³⁴,³⁵


Two Phase 1 Clinical Trials (NCT03076385 and NCT03345043) assessed mRNA vaccinations in opposition to the H10N8 and the H7N9 influenza viruses after preclinical research.³⁶ In healthy adults (18 to 64 years old for the H10N8 study and 18 to 49 years old for the H7N9 study), both trials demonstrated strong humoral immune responses and high tolerability for the recommended vaccination doses, providing protective concentrations of antibodies against the H10N8 and H7N9 influenza viruses.³¹

Co-administration of a quadrivalent influenza vaccination high dosage and mRNA-1273 vaccination to people who are 65-years of age or older has been accepted in a phase 2 experiment (NCT04969276). The COVID-19 vaccine response was unaffected by the vaccine, which produced immunological responses against all the four influenza strains (A H1N1, A H3N2, B Yamagata, and B Victoria). For older persons, this co-administration provides a safe way to guard against COVID-19 and influenza.³⁷


Zika virus

The Zika virus is a flavivirus transmitted by Aedes mosquitoes that causes Guillain-Barré syndrome in adults and, in rare cases, severe neuropathology in infants.³⁹,⁴⁰ Global health concerns were highlighted by the Zika virus pandemic in the United States in 2015, which was spread by autochthonous transmission.⁴¹ Numerous Zika virus mRNA-LNP vaccine recipients were created as well as evaluated in pre-clinical research.⁴²⁻⁴⁴ At five weeks after vaccination, Pardi and colleagues demonstrated that a particular intradermal injection of mRNA that encodes for the pre-membrane and envelope glycoproteins (prM-E mRNA-LNP) produced potent neutralizing antibodies, shielding mice and nonhuman primates against the Zika virus obstacles.[42] In a similar manner, the Moderna mRNA-1893 vaccine produced strong neutralising titres of antibodies, shielding the mice from the deadly Zika virus obstacle.⁴³ Furthermore, mRNA vaccinations shielded mice from congenital illness and the spread of the Zika virus at the time of pregnancy.⁴⁴,⁴⁵

Additional clinical development of the Zika virus precursor bilayer and the coat of mRNA-LNP vaccination was prompted by encouraging preclinical results. mRNA-1325 and mRNA-189365, two mRNA vaccine candidates, participated in phase1 Clinical Trials (NCT03014089 and NCT04064905, respectively). Good acceptability was demonstrated by mRNA-1325; however, Zika virus-targeting neutralizing antibodies (nAb) results were subpar.⁴⁶

However, mRNA-1893 produced potent and long-lasting Zika-specific nAb responses in a variety of dosages and serostatuses, indicating that it should continue to be developed to combat the Zika virus.⁴⁷

The Zika mRNA-1893 vaccine is currently undergoing a Phase 2 Clinical Trial (NCT04917861) and has been provided a Fast Track status by the US Food and Drug Administration (FDA). There are 809 healthy volunteers in the continuing 2021–24 experiment, ranging in age from 18 to 65, from both indigenous and non-native flavivirus regions. For the subjects who are either flavivirus seronegative or flavivirus seropositive, the experiment assesses the protection, acceptance, and reactogenicity of the two doses of the mRNA-1893 vaccine in comparison to the placebo.



Rabies virus


Rabies, a zoonotic illness spread by contaminated animal saliva, is almost always lethal and is caused by the Rabies virus. Worldwide, canine Rabies causes around 50,000 fatalities per year. Given their affordability, mRNA vaccines present a viable way to speed up the prevention of rabies, especially in low-income nations. Protamine was used as a stabilizing agent and adjuvant in the formulation of the primary mRNA Rabies vaccine, CV7201, which consists of the rabies virus’s glycoprotein, as well as producing protective, long lasting immunological responses that are adaptive in mice, pigs, and non-human primates. LNP-formulated vaccine CV7201 mRNA additionally demonstrated benefits throughout the proton method, suggesting that it could be a practical and affordable way to prevent Rabies.⁴⁸⁻⁵⁰

In healthy adults between the ages of 18 and 40, the CV7201 mRNA-LNP vaccination was assessed in the Phase 1 Clinical Trial (NCT02241135). Utilising a normal syringe with a needle or an injector that is needleless, different study groups were given different dosages (80 to 640 µg) and methods of administration (intramuscular or intradermal). In all groups, the CV7201 vaccination elicited a dose-dependent immunological response and was safe and well tolerated.⁵¹ In the Clinical Trial (NCT03713086), healthy subjects between the ages of 18 and 40 reported that minimal doses of 1 µg or 2 µg of the unaltered mRNA-LNP rabies vaccine CV7202 were effective and well accepted.

All vaccine recipients had robust nAb responses, reaching the WHO-endorsed protective threshold of ≥0·5 IU/ml.⁵² Additional research is necessary to optimally formulate and administer the mRNA-LNP rabies vaccine, but these trials indicate that it may be a promising substitute for conventional vaccines for rabies protection, especially in settings with low resources.


TABLE

Active and completed clinical trials of mRNA vaccines in the treatment of viral infections,

Infection

Phase

Status

Drug Treatment

NCT number

HIV

I / II





I



II

Completed





Terminated



Completed

mRNA-transfected autologous DCs+/- autologous DCs with no mRNA transfection


TriMix mRNA+/- HIV mRNA


iHIVARNA-01 + TriMix+/-Placebo

NCT00833781





NCT02413645



NCT02888756

Tuberculosis

I

Completed

GSK 692342

NCT01669096

Influenza

I



I / II

Completed



Recruiting

VAL-506440 + placebo


mRNA-1010 + placebo

NCT03076385



NCT04956575

Zika virus

I



I

Completed



Active

mRNA-1325 + placebo


mRNA-1893 + placebo

NCT03014089



NCT04064905

Rabies virus

I




I

Completed




Active

CV7201 mRNA encoding the rabies virus glycoprotein


Rabipur

NCT02241135




NCT03713086


CANCER VACCINES

mRNA vaccines, a novel cancer treatment, encode antigens for tumours, consisting of tumour-specific antigens (TSAs) and tumour-associated antigens (TAAs), immunomodulatory molecules, or a combination of these, to trigger and fine-tune the immune response against cancer. ⁵³⁻⁵⁵ Target cancer antigens that are overexpressed and found in healthy cells are called TAAs. T-cell resistance to the host antigens reduces the effectiveness of TAA-based vaccinations.⁵⁵⁻⁶⁰ TSAs, on the other hand, have higher anti-tumour specificity and potency and are exclusively expressed in the malignant tissue. TSAs, which are caused by somatic mutations in cancer cells, are also known as neoantigens. ⁵³⁻⁵⁵

Companies such as BioNTech and Moderna invested to create customised vaccinations, that combined screening for neoantigen immunogenicity as well as high-throughput sequencing to find neoantigen candidates from the patient's tumour samples. From patient tumour harvesting to the production of vaccines, candidate discovery, assessment, evaluation and genotyping, these customised vaccines demand a quick transformational period. mRNA platform's capacity for quick manufacturing is advantageous to this procedure.⁵⁸,⁶¹ Conry and associates utilised mRNA preparations in liposomes that encodes the human CEA antigen to conduct the first preclinical proof-concept mRNA cancer vaccination trial in 1995. Numerous preclinical and clinical studies on mRNA-encoded TAA vaccinations have also been conducted after the introduction of mRNA vaccines.⁶² The four TAAs melanoma (NY-ESO-1, MAGE-A3, tyrosinase, and TPTE) encoded by BioNTech's mRNA–lipoplex vaccine candidate BNT111 can be given individually or combined with scheduled death receptor-1 (PD-1) inhibitor. BNT111 was recently granted Fast Track status by the US FDA as an experimental treatment for advanced melanoma, and it has demonstrated robust immune responses specific to antigens in patients with melanoma that is incurable.⁵⁸,⁶³ Adapting customised TAA panels derived from autologous tumours, that involved loading autologous dendritic cells with mRNA from the primary tumour tissue or specific TAAs, is another tactic employed using TAAs. Clinical trials for acute myeloid leukaemia (NCT00514189), prostate cancer (NCT01197625), as well as customised TAA panels (NCT01334047, NCT02709616, NCT02808364, and NCT02808416) are a few examples.⁵⁸,⁶⁴

There are tens to thousands of neoantigens present in the majority of tumour cells.⁵⁸,⁶⁵ BNT122 is a personalised, poly-neoepitopic mRNA vaccine that contains approximately 20 neoepitopes specific to patients and has been evaluated in the therapy of colorectal cancer (NCT04486378) as well as melanoma (NCT03815058). mRNA-4157 is an additional personalised vaccinations candidate encoded in LNPs that has been evaluated; it comprises of 34 neoantigens and has been studied in the treatment of patients having reconstructed solid tumours, such as melanoma, bladder carcinoma, and non-small cell lung cancer, whether alone or along with conjunction in the PD-1 immune checkpoint inhibitor pembrolizumab (Keytruda; NCT03313778).⁵⁸,⁶⁶ Together with impressive neoantigen-specific T-cell responses, mRNA-4157-containing monotherapy and in combination treatment with pembrolizumab demonstrated a tolerable safety profile. 12 out of 13 patients who had monotherapy were said to be free from disease.[67] Combining supportives, immune checkpoint inhibitors, cytokines, or agonist with antigen-encoding mRNA vaccines could enhance their usefulness.

The clinical safety as well as effectiveness of BNT151, a nucleoside advanced IL-12 mRNA, as single therapy or with combination to another anticancer treatments on patients having advanced solid tumours are being investigated in a phase 1/2 clinical trial (NCT04455620). The cohort's goal is to track drug-induced alterations in the tumour and blood as well as pharmacodynamic activity.⁶⁷ Another class of mRNA cancer vaccines is being studied; these vaccines encode immunomodulatory molecules that, when subjected into the tumour area, provide pro-inflammatory milieu which promotes memory responses and T-cell proliferation.⁵⁸,⁶⁸ Studies on the safety and effectiveness of the ongoing clinical trials have not yet been carried out.


THERAPEUTIC mRNA APPLICATIONS

Monogenic diseases and protein replacement

Mutations in a single gene can result in monogenic illnesses, which are hereditary genetic defects. Over 5000 monogenic illnesses have been found.⁶⁹ For the treatment of monogenic illnesses, there have been several strategies that were based on substrate, protein, mRNA, and DNA. Protein replacement therapy has always emerged as successful treatment option for various monogenic diseases by substituting either faulty or insufficient protein secretions; nevertheless, exogenous protein supplements present a number of difficulties, including minimal delivery efficacy, cellular or sub-cellular localisation issues, production difficulties, and high cost.⁷⁰⁻⁷²

In order to treat methylmalonic acidaemia, a rare illness ie. autosomal recessive metabolic disorder, caused by a shortage of enzyme methyl malonyl-CoA mutase, the malfunction of the cofactor adenosyl-cobalamin or deficiency in the enzyme methyl malonyl-CoA epimerase, Moderna developed mRNA therapeutics. Significantly increased methylmalonic acid concentrations, which result in metabolic instability, are the hallmarks of methylmalonic acidaemia.⁷³ Research on the delivery of MMU mRNA has shown promise. Mice with total methyl malonyl-CoA mutase deficiency were saved by weekly intravenous infusion of methyl malonyl-CoA mutase mRNA, which resulted in 60–90% decrease the methylmalonic acid in plasma.⁷⁴ Acute intermittent porphyria, that was brought on by porphobilinogen deaminase (PBGD) haploinsufficiency and resulted in the increased levels of neurotoxic haemoglobin precursor porphobilinogen as well as delta-aminolaevulinic acid, which has the ability to produce neuro-visceral episodes, is another condition for which 4 mRNA therapy is being researched.⁷⁵

Intravenous treatment in PDGB mRNA-LNP increased expression in PBDG and liver activity within two hours, and concentrations of PBDG were still recognised 10 days after delivery, according to the study conducted by Jiang and his colleagues. At 24 hours after injection, decreases in the levels of porphobilinogen and aminolaevulinic acid in the urine were noted. Repeat doses administered for every six weeks resulted in a sustained reduction in porphyrin precursors.⁷⁴,⁷⁵ Moderna have also worked on treatments based on mRNA for the crosslinked metabolic illness Fabry disease.

A lack of α-galactosidase A causes a gradual buildup of glycosphingolipids, which can cause organ failure and the clinical signs of heart, kidney, and brain disorders. One intravenous injection having LNP as well as α-galactosidase mRNA restored α-Gal enzymes in vital parts of body such as the heart, liver, spleen as well as kidney according to a study by Zhu and the colleagues.⁷⁶ For cystic fibrosis, an autosomal recessive genetic condition brought on by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, mRNA-based therapies are also being researched. Secretory epithelial cells having chloride efflux is disrupted by CFTR mutations, causing serious harm to the digestive and respiratory systems as well as promotion of multi-organ failure leading to death.⁷⁷⁻⁷⁹ Chloride secretion was restored in CFTR-knockout animals and patient-derived bronchial epithelial cells when Robinson and colleagues used LNP to deliver chemically modified CFTR mRNA. Chloride secretion was restored for at least 14 days after intranasal delivery of CFTR mRNA-LNP, with maximum activity occurring on the third day and restoration of chloride outflow about 50%.⁸⁰ Nebulized CFTR mRNA-LNP was used in the first clinical trial (MRT5005) by Translate Bio, which was shown to be safe, well tolerated, and free of significant side effects.⁸¹

Another target for mRNA-based therapies is haemophilia, which is a hereditary bleeding disorder caused by the mutation of the factor VIII (haemophilia A) or in the genes of the factor IX (haemophilia B).⁸²,⁸³

Although protein replacement therapy is relatively costly in comparison to other medications, it has proved successful in treating haemophilia. When Russick and colleagues gave FVIII-deficient mice B domain-deleted FVIII-mRNA, the correction to bleeding in an experimental haemophilia A model was observed. For more than 72 hours, the circulating factor VIII coagulant activity was 5% higher than usual.⁸⁴ In order to treat mice having FIX deficiency in a haemophilia B model, Ramaswamy and colleagues employed LNP-mediated treatment of mRNA factor IX (FIX). This resulted in the correction of the bleeding defect as well as a quick spike in the expression of FIX mRNA in 4-6 hours after being intravenously delivered that persisted for about 4 to 6 days.⁸⁵


Monoclonal antibodies and immunotherapeutic applications

The first-in-human clinical study (NCT03829384) was conducted on the security, pharmacokinetics as well as pharmacodynamics of mRNA-1944, an mRNA-LNP encoding the anti-Chikungunya virus mono-clonal neutralising antibody (CHKV-24), that was carried out by Moderna between 2019 and 2020. Concentrations in serum CHKV-24 increase depending upon the dose, the study discovered an acceptable safety profile that should be adequate to protect against human Chikungunya virus infection.⁸⁶,⁸⁷ Antibodies encoded with mRNA-LNP or mimics of antibodies were created in a work by Thran and associates to offer therapeutic and preventative defence against viral diseases such as influenza B and rabies, as well as toxins such as botulinum neurotoxin and the Shiga toxin.

Significant liver expression was found as early as two hours following intravenous delivery of heavy camelid chain-only variable neutralizing agents (VNAs) encoded by mRNA-LNP. Peak expression for anti-botulinum neurotoxin VNAs was observed at 24 hours, while for anti-Shiga toxin VNAs, it has been observed between 6 and 24 hours. The anti-botulinum toxin VNA's protective ability was demonstrated using an intoxication paradigm, in which all intoxicated animals survived whereas control mice did not. Antibodies encoded with mRNA-LNP have also been employed in passive immunotherapy to guard against HIV-1 challenge. An mRNA-LNP encoded with VRC01 predominantly neutralizing antibodies in defence to HIV-1, was created by Pardi and colleagues.⁸⁸ A particular systemic injection of mRNA-LNP produced a serum antibody concentration of 170 μg/mL 24 hours after treatment.

A single infusion of 0.5 mg/kg anti-HIV mRNA-LNP humanised mice results in full protection from intravenous challenge. This study demonstrated the strong anti-HIV-1 effectiveness of mRNA-based passive immunisation. Additionally, antibodies encoded with mRNA, antibodies mimics, bi-specific antibodies, and chimeric antigen receptor (CAR) T-cell treatments are being developed as mRNA-encoded medicines for cancer immunotherapy. Bispecific antibodies generated by mRNA were created by Stadler and associates to eradicate large tumours.⁸⁹ Bispecific antibodies based on recombinant proteins have a short half-life in serum and production difficulties. Aiming at the CD3 T-cell protein associated with receptor as well as TAA, such as Claudin-6 (CLDN6), that is present in the solid tumours including ovarian and malignancies in the testis, mRNA-encoded bispecific antibodies were produced.

Bi-specific antibodies that target CD3 and CLDN6 spiked in serum concentration six hours after intravenous delivery, and their expression persisted for many days. When the bi-specific antibodies encoded with mRNA, CD3 and CLDN6, were administered weekly to mice with OV-90 tumours, the tumours were completely eradicated, in contrast to the control animal’s tumour development.⁸⁹ BNT142 (BioNTech), which targets CLDN6 in solid tumours and CD3 on T cells, has just begun first-in-human clinical trials. BNT142 was administered to the first participant in an open-label, multicentre, ½ dose phase escalation situation, safety and pharmacokinetic studies, following the expansion of cohorts in patients having evolved solid tumours that were CLDN6-positive, according to BioNTech publications from July 2022.⁹⁰


Immunosuppression

mRNA therapies have potential use in immunological tolerance, allergies, and suppressive immunotherapy. In order to treat experimental autoimmune encephalomyelitis, a non-inflammatory mRNA vaccine was described by Krienke and associates⁹¹. Here, animals received systemic administration of m1ψ-evolved mRNA-encoded with myelin oligodendrocyte glycoprotein epitopes 35 to 55 enclosed in liposomes that were non-immunostimulatory, which led to accumulation in cells that display the ITGAX antigen. Autoreactive effector T cells specific to antigens decreased and regulatory T cells specific to antigens increased as a result of the non-inflammatory presentation and delivery of the m1ψ-modified mRNA encoded autoantigens.⁹¹ Treatment for a variety of autoimmune illnesses may be significantly impacted by these platforms that induce tolerance.

In a Phase 1 clinical trial, Moderna has started analysing the pharmacokinetics, security as well as tolerability of mRNA-6231, an mRNA-LNP that codes for the human-serum albumin-IL-2 mutein fused protein (NCT04916431). [92,93] The cytokine IL-2 generally promotes T-cell proliferation as well as improved effector T-cell activity. However, murine IL-2 variants that selectively increased regulatory T-cell efficacy with decreased effector T-cell activity were produced using cytokine engineering.⁹⁴ PD-L1 is encoded by the mRNA-LNP 124mRNA-6981. Myeloid cells with increased PD-L1 surface expression may serve as signals that co-inhibit self-reactive lymphocytes.


Genomic editors

The underlying causes of genetic illnesses may be treated by gene therapy using techniques based on mRNA, virus or DNA, perhaps providing a permanent cure. Adeno-associated virus and other viral gene therapy techniques have made great strides in the curing of mono-genic disorders. Adeno-associated virus is linked to produce both innate as well as adaptive immunological responses, necessitates nuclear administration and carries the task of genomic integrity. By introducing therapeutic genes or fixing genetic flaws, evolution in gene editing has made it possible to terminate illness. Safer in vivo genomic modification is made possible by gene editing encoded with mRNA leading to high editing efficiency and reduced off-target consequences.⁹⁵,⁹⁶

In-vivo CRISPR-Cas9 gene editing has been employed in a clinical trial to treat TTR amyloidosis, which is brought on by the buildup of faulty protein in tissues ie. transthyretin. The TTR protein was reduced roughly by 52% following a dose of 0·1 mg/kg and by about 87% at a dose of 0·3 mg/kg after a single treatment of LNP-mediated inculcating of Cas9 mRNA and sgRNA, a noteworthy accomplishment demonstrating the therapeutic efficacy of mRNA CRISPR-Cas9-based therapeutics targeted ablation of the TTR gene.⁹⁷ At one year following treatment, the high-dose individuals still had a lower TTR and no symptoms of illness.⁹⁸

Fusion of cytidine or adenine deaminase to an inactive Cas9 converts cytosine–thymine base to thymine–adenine base or adenine–thymine base to guanine–cytosine base. Adenine base editing has become the most recent adaptation of the CRISPR-Cas9 system to reduce errors in single-nucleotide bases. This base editing process was utilised to modify the adenine base of PCSK9 in vivo.

Adenine base editors mRNA and a sgRNA that targeted PCSK9 were administered to mice and cynomolgus macaques by LNP-mediated delivery. Base editing of up to 67% in mice and up to 34% within macaques resulted in a persistent reduction in LDL values of approx. 58% within mice and approx. 14% within macaques. Off-target mutations were not induced in order to accomplish transient genome editing.⁹⁹ Targeted mRNA delivery technologies in conjunction with genome editing advancements hold enormous promise for more straightforward therapeutic approaches. Haematological illnesses like sickle cell anaemia, for which some 300,000 babies are born annually within areas having limited approach to cutting-edge treatments, are one area where genetic editing therapies may be very helpful.


SAFETY CONSIDERATIONS AND POTENTIAL BARRIERS

It has been determined that COVID-19 mRNA vaccinations, including mRNA-1273 and BNT162b2, are safe and efficacious.¹⁰⁰ As of 3rd August 2022, more than 12 billion doses of vaccinations had been administered globally.¹⁰¹ The acceptance of the mRNA-LNP vaccines has been facilitated by nucleoside alteration, mRNA sequence editing and low toxicity of the lipid components.¹⁰² By avoiding the toxicity issues associated with cationic lipids and cationic polymers, ionisable lipids in particular have been able to preserve the efficiency of cargo transport.¹⁰³,¹⁰⁴ Mild local and systemic reactogenicity have been the most common side effects of the mRNA vaccine that have been reported.¹⁰² In general, mRNA-LNP platforms are demonstrated to be protective, having advantages that greatly outweigh hazards, despite the uncommon occurrence of serious disorders such as anaphylactoid responses and cardiomyopathy.¹⁰⁰,¹⁰⁵,¹⁰⁶,¹⁰⁷ How to build mRNA-LNPs safely while achieving their therapeutic goals must be taken into account as the shift from vaccine to non-vaccination therapeutic uses develops. The requirements for significantly high doses of mRNA-LNPs, mode of delivery (likely IV injection as opposed to local IM administration), advancement in the LNP system provides specificity in cell or organ targeting, as well as the impact of higher mRNA-LNP dose to people with already existing inflammatory or chronic pathological situations, are just a few of the stark differences between mRNA-LNPs and mRNA-LNP vaccinations. As a result, we expect that therapeutic mRNA-LNPs will need to meet higher safety standards in order to be approved by the FDA. The upcoming generations of mRNA therapeutics will need to be planned with utmost care, with the upgraded therapeutic system and improved factors should be taken into consideration.



Conclusion

A revolutionary change in the way we treat and possibly even cure diseases is being ushered in by mRNA-based medicine. Although mRNA technology has improved stability, decreased immunogenicity, and improved expression, there still remain challenges that must be addressed to completely eliminate the possibility of negative side effects and to increase expression, stability, and duration in order to perhaps make commercially available mRNA medication possible. Higher standards must also be fulfilled in order to move to non-vaccine applications, since more development is required to create effective, targeted mRNA therapeutic platforms that can assure safe administration of the mRNA medication into the targeted cells beyond experiencing toxicity, immunogenic capacity or off-target biodistribution problems. According to reports, this is possible. We anticipate the creation of a new class of mRNA medications that are optimised to tackle the issues raised and cure illnesses that were once believed to be non-treatable.


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Author Information


Authors:

Anubhi Yadav, Akanksha Dwivedi, G. N. Darwhekar


Acropolis Institute of Pharmaceutical Education and Research, Indore 453771, M.P., India


Corresponding Author:

Dr. Akanksha Dwivedi

Address: Acropolis Institute of Pharmaceutical Education and Research, Indore 453771, M.P., India

Telephone: 9993840688




 
 
 

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