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MRNA therapeutics

From EverybodyWiki Bios & Wiki




mRNA-based therapeutics rely on the principle that mRNAs encoding certain peptides or proteins elicit their transient expression in the cytoplasm. This induces the expression or degradation of specific intracellular proteins to achieve therapeutic disease effects at the cellular level. In recent years, mRNA has evolved into a promising new class of drugs with the potential to treat a variety of diseases with highly unmet medical needs.

Messenger RNA (mRNA) is a single-stranded RNA molecule that is complementary to one of the DNA strands of a gene...[1] An mRNA molecule transfers small fragments of DNA code that are used to make proteins.[2] Unlike DNA therapeutics, mRNA therapeutics do not need to enter the nucleus to be effective because they are translated as soon as they reach the cytoplasm, due to the difference in functional sites of action.[3] In addition, mRNAs are not integrated into the genome and therefore do not carry the same risk of insertional mutations as plasmids and viral vectors,[4] which makes them suitable for cancer vaccines, tumor immunotherapy, and infectious disease prevention.[5][6]

Discovery and Development

The work of Elliot Volkin and Lazarus Astrachan in 1956, when they infected E. coli with T2 phages and placed them in medium containing 32P, found clear signs of mRNA in the changes in protein synthesis.[7] [8][9]In May 1961, researchers Sydney Brenner, François Jacob, and Jim Watson, with whom they collaborated, reported the isolation of mRNA.[10][11]In the decades following the discovery of mRNA, attention was focused on understanding the structural, functional, and metabolic pathway aspects of mRNA. In recent years, the potential of mRNA as a therapeutic agent has been more explored. In 1990, Jon A. Wolff demonstrated the idea of nucleic acid-encoded drugs by direct injecting in vitro transcribed (IVT) mRNA or plasmid DNA (pDNA) into the skeletal muscle of mice which expressed the encoded protein in the injected muscle. [12][13][14][6] In 1995, Robert M. Conry and Albert F. LoBuglio constructed mRNA transcripts encoding luciferase and human carcinoembryonic antigen (CEA) which are capped, polyadenylated, and stabilized by human β-globin 5′ and 3′ untranslated regions, which is the first vaccination with mRNA encoding cancer antigens.[15] By 2013, CRISPR cas9 technology revolutionized gene editing[16]

Over the past few decades, medical researchers have demonstrated the feasibility and benefits of mRNA-based interventions through proof-of-concept. In fact, there are currently more than 65 mRNA-based therapies and more than 85 mRNA vaccines in development. In vitro transcribed (IVT) mRNAs are now being evaluated as therapeutic options for several oncological and genetic diseases. Furthermore, experts believe that while such product categories are forthcoming, their prospects may be limitless.[17]

In recent years, the COVID-19 pandemic has led medical researchers to further recognize the great potential of mRNA-based vaccines. Unlike conventional vaccinology, these vaccines do not require the use of live (attenuated) pathogens. On top of that, since mRNA does not enter the nucleus when it acts, this means that it cannot react adversely with the patient's genome. In this context, it is worth mentioning that, for the first time in the history of vaccine development, mRNA vaccines against novel coronavirus strains developed by Pfizer/BioNTech (COMIRNATY®/BNT-162) and Moderna (SpikeVax/mRNA-1273) were developed and approved for use within one year.[17]

Mechanisms

In vitro transcription(IVT) is performed on a linearized DNA plasmid template containing the targeted coding sequence. Then, naked mRNA or mRNA complexed in a nanoparticle will be delivered systemically or locally. After then, a part of the exogenous naked mRNA or complexed mRNA is going through cell-specific mechanisms. Once in the cytoplasm, the IVT mRNA is translated by the protein synthesis machinery.[18][19]

There are two identified RNA sensors, toll-like receptors (TLRs) and the RIG-I-like receptor family. TLRs are localized in the endosomal compartment of cells, such as DCs and macrophages.[20] RIG-I-like family is as a pattern recognition receptor (PRR).[21] However, the immune response mechanisms and process of mRNA vaccine recognition by cellular sensors and the mechanism of sensor activation are still unclear.[19][6]

Nano Delivery Systems

The main problems in delivering mRNA are the intrinsic instability of the molecule and the interference of RNases, which significantly affect the persistence in vivo. In addition, the targeted delivery of this relatively fragile biomolecule in vivo is complicated. Over the years, attempts to modify the chemical structure of mRNA have enabled therapists to design relatively more stable versions of the molecule. Various techniques, including electroporation, gene guns, and in vitro transfection, allow intracellular delivery of mRNA in culture dishes.[17][22] However, in vivo applications require mRNA nano-delivery systems that transfect immune cells without causing toxicity or unwanted immunogenicity. Liposomes and lipid-based nanoparticles have successfully administered mRNA-based vaccines.[17]

Lipid-Nanoparticle

Currently, LNPs are the main non-viral delivery vectors for gene therapy.[23] LNPs are biocompatible phospholipid monolayer structural vectors encapsulating mRNA in lipid cores to avoid degradation[24]. In addition to negatively charged mRNA, LNPs generally have four components: ionizable cationic phospholipids, neutral auxiliary phospholipids, cholesterol, and polyethylene glycol-modified phospholipids. Cholesterol has a strong membrane fusion capacity and promotes intracellular uptake and cytoplasmic entry of mRNA[25]. pEGylated phospholipids are located on their surface to enhance their hydrophilicity, avoid rapid clearance by the immune system, prevent particle aggregation, and increase stability[26]. The presence of carboxylic acid esters ensures the degradability of phospholipids in vivo and avoids toxic side effects due to phospholipid accumulation[27]. Laboratory studies of LNP have shown many results in reducing poisonous effects in drug delivery for cancer therapy.[28][29]For example, IL-2

The development of mRNA delivery via LNP is very fast. Currently, many companies are developing mRNA LNP products for different diseases. Although LNP is one of the most effective means of mRNA delivery, countless parameters can be modified to achieve efficient, non-toxic, and tissue, organ, or cell-specific LNP formulations. Moreover, due to poor stability, mRNA-LNP is expensive to transport and store, and its long-term storage is an essential but still pending issue in the future of LNP development.

Liposome

Liposomes are spherical closed vesicles formed by phospholipid bilayers.[30][31] They were first discovered by A. D. Bangham in 1965 and have long been used to deliver small-molecule drugs with particle sizes ranging from 20 nm to 1000 nm.[32][33] Cationic liposomes are positively charged, consist mainly of cationic lipids, and can target nucleic acids efficiently.[34][35] By changing the physical and chemical properties of cationic liposomes, such as modifying the surface of cationic liposomes and adjusting the particle size, good pharmacokinetic properties can be obtained in vivo.[36] In general, liposome preparation methods include film dispersion, solvent injection, freeze-drying, and pH gradient methods.

There are many advantages of delivering mRNA by liposomes:

  1. Liposomes are spherical vesicles that can encapsulate mRNA and resist degradation by nucleases.
  2. As a delivery system, liposomes are not host-restricted.
  3. Liposomes can easily fuse with recipient cells with high transfection efficiency.
  4. The bilayer membrane structure of phospholipids highly mimics the cell membrane. It is a stable structure known in biological evolutionary theory and has good long-term storage stability.

Huang et al. constructed RBD-encoding mRNA (LPX/RBD-mRNA) formulated in liposomes that could express RBD in vivo and successfully induced SARS-CoV-2 RBD-specific antibodies in inoculated mice then efficiently neutralized SARS-CoV-2 pseudotyped virus.[37]

Currently, liposome-based therapies have been applied to cancer chemotherapy, ophthalmic disorders, vaccine, and gene delivery.[38] Despite these advantages and wide application, liposome preparation and mRNA encapsulation production are much more complex than LNP.[39]

Polymer Complexes

Polymeric materials are high molecular weight (usually up to 10-106) compounds composed of simple structural units repeatedly linked by covalent bonds. Typical such materials are chitosan, polyethyleneimine, polyurethane, etc. To improve their transfection efficiency and stability, most of the polymeric materials used for mRNA delivery need to be modified.[40] For example, polyethyleneimine (PEI) systems successfully deliver mRNA to cells[41] and in the nose[42]. In addition, PEI-based systems improved the response of skin explants[43] and mice[44] to sa-mRNA vaccines.

Cationic Peptides

Peptide-based delivery is a less explored system, as only proteases have been evaluated in clinical trials[45]. Novel delivery approaches include the use of cationic cell penetrating peptides (CPPs) and anionic peptides. the CPPs system has been shown to improve T cell immune responses in vivo[46], modulate innate immune responses, and enhance protein expression in DC and human cancer cells in vitro.[47][48] Conjugated mRNA multimers with anionic peptides exhibit increased cellular uptake in DC cells while not inducing cytotoxicity.[49]

Coolen et al. developed an alternative lipid-based mRNA delivery system utilizing poly(lactic acid) nanoparticles (PLA-NPs) and cationic cell-penetrating peptides as mRNA condensation agents. The formulation was assembled in two steps. It modulates the innate immune response of DCs by activating endosomal and cytoplasmic pattern recognition receptors (PRRs) and induces markers of adaptive responses in primary human DCs in vitro.[50]

Applications

Cancer Immunotherapy[6]

In 1995, Robert Conry demonstrated that intramuscular injection of naked RNA encoding carcinoembryonic antigen elicited antigen-specific antibody responses.[51]Then, it was elaborated by demonstrating that dendritic cells(DCs) exposed to mRNA coding for specific antigens or to total mRNA extracted from tumor cells and injected into tumor-bearing mice induced T cell immune responses and inhibited the growth of tumors.[52] Then, researchers started to approach mRNA transfected DCs using vaccines based on ex vivo IVT mRNA-transfected DCs.[53] Meanwhile, Argos Therapeutics had initiated a Phase III clinical trial using DCs with advanced renal cell carcinoma in 2015 (NCT01582672) but it was terminated due to the lack of efficacy.[54]

For further application, IVT mRNA was optimized for in situ transfections of DCs in vivo. It improved the translation efficiency and stability of IVT mRNA and enhanced the presentation of the mRNA-encoded antigen on MHC class I and II molecules.[55][56] Then, they found out that the direct injection of naked IVT mRNA into lymph nodes was the most effective way to induce T cell responses.[57] Based on this discovery, first-in-human testing of the injection of naked IVT mRNA encoding cancer antigens by BioNTech has started with patients with melanoma (NCT01684241).[58]

Recently, the new cancer immunotherapy, the combining of self-delivering RNA(sd-rxRNA) and adoptive cell transfer(ACT) therapy, was invented by RXi Pharmaceuticals and the Karolinska Institute. In this therapy, the sd-rxRNA eliminated the expression of immunosuppressive receptors and proteins in therapeutic immune cells so it improved the ability of immune cells to destroy the tumor cells. Then, the PD-1 targeted sd-rxRNA helped increasing the anti-tumor activity of tumor-infiltrating lymphocytes (TIL) against melanoma cells.[59][60] Based on this idea, the mRNA-4157 has been tested and passed phase I clinical trial.[61]

Cytosolic nucleic acid-sensing pathways can enhance immune response to cancer. RIG-I agonist, stem loop RNA(SLR)14. Tumor growth was significantly delayed and extended survival in mice. SLR14 improved antitumor efficacy of anti-PD1 antibody over single-agent treatment. SLR14 was absorbed by CD11b+ myeloid cells in the tumor microenvironment. Genes associated with immune defense were significantly up-regulated, along with increased CD8+ T lymphocytes, NK cells, and CD11b+ cells. SLR14 inhibited nonimmunogenic B16 tumor growth, leaving immune memory.[62]

Heart Diseases

In 1990, direct injection of mRNA could be translated into protein in vivo was first demonstrated[63]. The therapeutic value of mRNA is limited because it can be recognized by various pattern recognition receptors (PRRs) to stimulate innate immune responses[64]. Therefore, chemically modification is used to its vector or its structure to avoid immunostimulatory activity and improve translatability and stability. The major mRNA-based approaches are growth factor delivery to improve vascularization and inhibition of inflammation[65]. By delivering an mRNA encoding human VEGF into infarcted mouse hearts, new blood vessels around ischemic areas were introduced[66]. At present, introducing specific cytokines to promote cardiac myocyte regeneration is a novel emerging therapeutic approach[67]

Anti-viral

In 2021, COVID-19 has caused a worldwide challenging and threatening pandemic, with huge health and economic losses. SLR14 was reported to prevent infection in the lower respiratory tract and severe disease in an interferon type I (IFN-I)–dependent manner in mice. Immunodeficient mice with chronic SARS-CoV-2 infection experienced near-sterilizing innate immunity with no help from the adaptive immune system.[68][6]

Vaccines

In 1993, the first success of an mRNA vaccine was reported in mice, by using liposome-encapsulated IVT mRNA which is encoding the nucleoprotein of influenza that induced virus-specific T cells.[69] Then, IVT mRNA was formulated with synthetic lipid nanoparticles and it induced protective antibody responses against the respiratory syncytial virus(RSV) and influenza virus in mice.[70]

There are a few different types of IVT mRNA-based vaccine development for infectious diseases. One of the successful types is using self-amplifying IVT mRNA that has sequences of positive-stranded RNA viruses. It was originally developed for a flavivirus and it was workable with intradermal injection. One of the other ways is injecting a two-component vaccine which is containing an mRNA adjuvant and naked IVT mRNA encoding influenza hemagglutinin antigen only or in combination with neuraminidase encoding IVT mRNA.[71]

For example, for the HIV treatment, vaccines are using DCs transfected with IVT mRNA that is encoding HIV proteins. There are a few phase I and II clinical trials using IVT mRNA encoding combinations and it shows that antigen-specific CD8+ and CD4+ T cell responses can be induced. However, no antiviral effects have been observed in the clinical trial.[72][73]

In human trials conducted by Moderna, intramuscular vaccines against avian influenza A viruses H10N8 and H7N9 have been shown to be safe and immunogenic.[74]

Another example is the prevention of Zika virus. Pardi proposed a bivalently modified mRNA vaccine encoding the pre-membrane and envelope glycoproteins of the Zika virus strain[75]. A single dose of the vaccine, encapsulated in LNPs and administered intradermally, was sufficient to protect mice from viral attack for two weeks or five months after vaccination and was sufficient to protect nonhuman primates for five weeks after vaccination. using the same antigen, Moderna developed an unmodified, encapsulated mRNA-1893 vaccine to combat Zika virus, which quickly received FDA approval for follow-up experiments to assess its safety, tolerability, and immunogenicity.[76]

One of the other mRNA vaccines is for COVID-19. The Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) outbreaks in December 2019 and spread all over the world, causing a pandemic of respiratory illness designated coronavirus disease 2019 (Covid-19).[77] The Moderna COVID-19 vaccine, manufactured by Moderna since 2020, is a lipid nanoparticle (LNP) encapsulated mRNA-based vaccine that encodes for a full-length, prefusion stabilized spike(S)-2P antigen of SARS-CoV-2 with a transmembrane anchor.[78]  A lower incidence of adverse reactions was reported for BNT162b2 compared to mRNA-1273; however, mRNA-1273 was more stable in transport and storage. For nursing home residents in the United States, the anti-infective effect of two doses of mRNA vaccine was 74.7% (March-May 2021). Between June and July 2021, when circulation of the B.1.617.2 (Delta) variant dominated, effectiveness dropped significantly to 53.1%.[79] Nevertheless, mRNA vaccines remain the vaccines with the shortest development and application cycles and are expected to be rapidly upgraded for new variants.[6]

Tissue Regeneration

A 2022 study by researchers from the Mayo Clinic, Maastricht University, and Ethris GmBH, a biotech company that focuses on RNA therapeutics, found that chemically modified mRNA encoding BMP-2 promoted dosage-dependent healing of femoral osteotomies in male rats. The mRNA molecules were complexed within nonviral lipid particles, loaded onto sponges, and surgically implanted into the bone defects. They remained localized around the site of application. Compared to receiving rhBMP-2 directly, bony tissues regenerated after mRNA treatment displayed superior strength and less formation of massive callus.[80][6]

Limitations

There are many challenges to the successful translation of mRNA into drugs because mRNA is a very large and heavy molecule (105 ~ 106 Da). Moreover, mRNA is unstable and easily degraded by nucleases, and it also activates the immune systems.[81] Furthermore, mRNA has a high negative charge density and it reduces the permeation of mRNA across cellular membranes.[82] Due to these reasons, without the appropriate delivery system, mRNA is degraded easily and the half-life of mRNA without a delivery system is only around 7 hours.[83] Even though some degrees of challenges could be overcome by chemical modifications, delivery of mRNA remains an obstacle. The methods that have been researched to improve the delivery system of mRNA are using microinjection, RNA patches (mRNA loaded in a dissolving micro-needle), gene gun, protamine condensation, RNA adjuvants, and encapsulating mRNA in nanoparticles with lipids.[81][84][85]

Even though In Vitro Translated (IVT) mRNA with delivery agents showed improved resistance against degradation, it needs more studies on how to improve the efficiency of the delivery of naked mRNA in vivo.[86]

The COVID-19 pandemic and the rapid development of a vaccine still put mRNA technologies on the map, showing their unique advantages at a critical time. These technologies have been arrived at through years of hard work by scientists in academia and industry. While many questions remain, mRNA therapeutics are poised for a myriad of possibilities moving forward into a potential future.

References

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