As the mRNA vaccine has achieved great results in the prevention of COVID-19, it has been widely recognized by global researchers. At the same time, the application prospect of mRNA technology in other diseases has also begun to receive a lot of attention, including tumors, autoimmune diseases, heart disease, rare diseases, and other conventional diseases.

In the field of treatment of autoimmune diseases, the disease itself is mostly caused by autoreactive T lymphocytes’ destroying self-tolerance and tissue damage. The current treatment methods may lead to systemic immunosuppression and increase the risk of side effects, such as infection. The latest research shows that mRNA technology can turn on immune regulation by expanding regulatory T cells (Treg) and engineered CAR-T cells, and finally achieve the therapeutic effect on autoimmune diseases.

Self-tolerance Induced Strategy

There is an urgent scientific problem in the treatment of autoimmune diseases, that is, how to inhibit the autoimmune response of pathogenic T cells without systemic immunosuppression. One of the key challenges is to safely and effectively deliver self-antigen to antigen-presenting cells (APCs) under non-pro-inflammatory conditions, so that the immune system can restore its self-recognition function and stop self-attack, that is, to achieve self-antigen-specific immune tolerance.

In the past, researchers have developed various methods, including the use of DNA, synthetic peptides, recombinant proteins, coated nanoparticles, or immunomodulatory cell therapy, to deliver autoimmune antigens. However, the road of transformation is still a long way off, and the progress of clinical trials is slow, mainly due to the polyclonal complexity of autoimmune diseases driven by patients’ unique and diversified library of autoreactive immune cells. This difference between individuals requires personalized treatment based on the patient’s autoantigen immune map, or the use of therapy that mediates bystander tolerance to suppress autoimmune lymphocytes, so as to avoid widespread immunosuppression.

The feasibility of RNA delivery to induce autoimmune tolerance in the human body is proved by the fact that the induction and maintenance of peripheral tolerance is based on the presentation of self-antigen by lymphoid APCs, the study about the use of RNA to deliver antigens, and recent research on mRNA vaccine of COVID-19. In 2021, the University of Mainz in Germany and BioNTech Company in Germany jointly developed a vaccine that can prevent autoimmune system diseases based on the principle of mRNA. They used disease antigen-encoding 1-methyl pseudouracil modified mRNA (M1 ψ mRNA) lnpLNP to deliver antigens to CD11c+APCs where lymphoid tissues reside without proinflammatory costimulatory signals, thereby activating Toll-like receptor (TLR) signals, inducing high levels of IFN- α and then activating Th1 cell responses. By introducing 1-methyl pseudouridine (M1 ψ) to replace uridine (U) in the process of transcription in vitro, TLR7 signal can be weakened, inflammation can be reduced, and antigen-specific immune tolerance can be induced. Moreover, this M1 ψ mRNA vaccine can effectively control the disease by reducing effector T cells (Teff) and increasing Treg in a variety of experimental spontaneous encephalomyelitis (EAE) mouse models. It is worth noting that these Treg can not only induce strong immune tolerance, but also perform a strong bystander immune tolerance function (bystander tolerance), which can improve EAE induced by homologous and non-homologous autoantigens. The vaccine has been successfully tested in mice and the results are published in the journal Science.

Of course, there is still a long way to go before the vaccine is approved. For humans, there are still three stages of experiments to determine the safety and efficacy of the vaccine. However, researchers see great potential for immunomodulatory mRNA vaccines. Since mRNA vaccines can be produced quickly, they can quickly adapt to antigens present in individual patients, which means that personalized therapy may be achievable.

Coding Biased IL-2 mRNA

Studies have confirmed that low-dose IL-2 has been proved to be an effective method for the prevention of allograft rejection and the treatment of autoimmune inflammation. However, it is well known that research on therapeutic IL-2 faces some challenges, such as short half-life and uncertain safe dose level. In addition, the trend of non-specific binding to stimulate the production of antibodies may also affect the efficacy of drugs or natural IL-2. Based on the in vivo expression characteristics of mRNA, IL-2 can establish a production plant in the target site, which can not only produce cytokines continuously, which is conducive to the long-term activity of IL-2, but also reduce its peak serum concentration and avoid the toxicological effects of high dose.

Moderna has used mRNA encoding biased IL-2 (fusion of human serum albumin) to selectively expand regulatory T cells to enhance their role in the treatment of autoimmune diseases. On August 2, 2021, Moderna completed the first drug administration in phase I clinical trial of mRNA therapy. mRNA-6231 is an mRNA-based therapeutic agent encapsulated by lipid nanoparticles (LNP), which can encode an interleukin-2 (IL-2) mutant protein fused with human serum albumin (HSA-IL2m). IL-2 is a pluripotent cytokine and a key survival factor of Tregs. It maintains the inhibition or amplification of Tregs by promoting the expression of Foxp3 (Treg family transcription factor) and the subsequent production of immunomodulatory cytokines. This biased immunoregulation is considered to play a key role in restoring immune homeostasis. mRNA-6231 is the company’s first candidate drug for the treatment of autoimmune diseases in clinical development and the first subcutaneous therapy.