Messenger RNA (mRNA) is a single-stranded molecule that carries genetic information from deoxyribonucleic acid (DNA) to ribosomes. Ribosomes then decode the genetic information and synthesize proteins. The mRNA-based therapies that we are going to discuss are drugs that use mRNA to treat or prevent diseases (mRNA-based therapy).
In recent years, the in vitro transcription (IVT) mRNA technology has attracted the interest and attention of scientists from research institutions and biopharmaceutical companies. Biopharmaceutical companies use mRNA-based technology platforms to develop drugs with targeted delivery methods, making drugs more precise and personalized. And with the help of genetic engineering, researchers can use synthetic mRNA to express specific proteins. Since synthetic mRNA is structurally similar to natural mRNA, it allows patients to produce therapeutic proteins in their own bodies, and reduces various troubles caused by the complex manufacturing process of recombinant proteins. The diversity of mRNA-based therapies enables drug developers to use synthetic mRNA as a tool for disease treatment, and has made progress in the research of cancer immunotherapy, stem cell therapy and infectious disease control, especially during the COVID-19 pandemic, mRNA technology has obvious advantages in vaccine development.
In the 1960s, molecular biology made great progress. The discovery of messenger RNA (1961), the successive discovery of RNA-related replicase (1962) and reverse transcriptase (1970), and the discovery and application of RNA splicing and catalytic ribozymes (1977, 1982) directly or indirectly promoted the development of mRNA-based new drugs. After more than 30 years of scientific advancement, RNA-based drugs were tested in animals for the first time. The first study using mRNA molecules for therapeutic purposes was published by Wolff et al. in 1990, which is recognized as the earliest application. In this study, IVT mRNA was directly injected into mouse skeletal muscle and expressed the encoded protein. The article pointed out that since RNA and tissues can be repeatedly obtained, RNA-based therapy can transfer the determined reversible type of gene transfer into the patient's cells to prevent or treat specific diseases. Subsequently, a series of milestone experiments revealed the potential of RNA-based therapy, including injecting influenza mRNA to induce immune response in mice (1993), injecting mRNA vaccine for anti-cancer research in mice (1995), using modified RNA to inhibit hepatitis C virus in mice (2002) and other breakthrough studies. These research methods and results have improved the development of mRNA-based therapy in different fields.
The improvement of lipid nanoparticle (LNP) carrier technology also greatly promoted the development of mRNA-based therapy. LNP is an emerging drug carrier, which has also extended its application to other fields of innovation and development, such as medical imaging. The earliest nanodrug delivery platform from concept to clinical application is liposome. Because liposomes can transport hydrophobic or hydrophilic molecules, including small molecules, proteins and nucleic acids, they have become a widely used carrier platform. In the development of anti-tumor drugs, liposomes reduce the side effects of carrying drugs and improve the patient's tolerance, but they do not significantly improve the patient's survival rate. In the early 1990s, with the development of nanoscience and nanotechnology, LNP gradually began to be used. Generally speaking, lipid nanoparticles and liposomes have similar designs. They are both lipid nanosystems and drug delivery carriers. They can protect drugs from being destroyed by human immune system, mimic biological membranes and allow drugs to have more time to reach predetermined targets. Secondly, they have the ability to help dissolve highly lipophilic molecules or regulate the pharmacological properties of drugs, thereby minimizing drug-induced side effects and improving drug safety. LNP and liposomes are slightly different in composition and function, and their applications are more diversified.
In the past 20 years, mRNA-based technology development for cancer treatment has gradually attracted attention and been fully developed. After continuous optimization, mRNA technology has made remarkable progress in cancer, rare diseases, genetic diseases and infectious diseases. In August 2018, the first siRNA-based drug Patisiran was approved by FDA for the treatment of polyneuropathy due to hereditary transthyretin amyloidosis (hATTR). This is a milestone approval for RNA-based therapy. siRNA is a short double-stranded RNA that can be split into single strands and bind to its predetermined target mRNA, causing predetermined target mRNA to break down and degrade, so it is also called RNA interference (RNAi) therapy.
Patisiran is an siRNA formulated into LNP that binds to apolipoprotein E (APOE) receptor and is absorbed by liver cells. It further cuts and degrades the mRNA that controls transthyretin protein by RNA interference, thereby reducing the production of transthyretin protein in circulation and its deposition in tissues and organs. In patients with ATTR amyloidosis, misfolded transthyretin protein accumulates in various tissues in the body, such as peripheral nerves and heart, causing organ and tissue damage, leading to neuropathy and cardiomyopathy. So far, in addition to Patisiran, three other RNAi drugs have been approved for use in the United States to treat certain rare diseases, such as acute hepatic porphyria (AHP), primary type 1 hyperoxaluria (PH1) and familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD).
In the past few years, mRNA-based therapy has achieved brilliant results in the field of infectious diseases, including using nucleoside-modified mRNA for immune therapy against human immunodeficiency virus (HIV), cytomegalovirus (CMV), human papillomavirus (HPV) and other infections.
During this period, the method of mRNA-based therapy in vitro transcription also gradually matured. There are two common and stable methods at present. One is to transfer mRNA in vitro to the patient's cells, and then transfuse these cells back to the patient. This method is widely used in gene engineering, gene reprogramming, or cell-based immunotherapy for cancer research. Another method is to directly deliver in vitro transcribed mRNA for research on tumor and infectious disease treatment, allergy tolerance and other protein replacement therapies. In addition to the above achievements in the treatment of rare diseases, mRNA vaccines also show their high efficiency and safety advantages in reducing COVID-19 infection and preventing its severity. Compared with traditional vaccines, synthetic mRNA vaccines are more effective, have no risk of integration into human DNA, and have the advantages of short development cycle, simple production process and low manufacturing cost, making mRNA vaccines more attractive in stimulating immune response, reducing infection rate or severity.
