Applications of mRNA Therapeutics

mRNA is a versatile device that can be utilized for therapeutic protein replacement, gene editing, cell therapy, vaccines, and more. Almost any protein can be introduced via mRNA, facilitating the cellular expression of gene editing tools or antigens as needed.

In recent years, great progress has been made in mRNA vaccine development, especially in individualized tumour vaccines. mRNA vaccines are a good approach as the generation process is simple, safety profiles are better than those of DNA vaccines, and mRNA-encoded antigens are readily expressed in cells. Productive entry of mRNA vaccines into human cells is a very challenging process. As an exogenous nucleic acid, naked mRNA is easily comprehended by the immune system and rapidly degraded by nucleases like RNases or microbial contamination after arriving the body. Thus, the pharmacological effects of utilizing naked mRNA as a vaccine are vastly lessened. That challenge is the key to successful mRNA manufacturing, purification, and formulation. To enhance the immune efficiency of mRNA vaccines, special delivery systems are required to protect administered mRNA from nucleases and allow delivery into cells.

Equipped with a team of professional scientists, Seattle Genova is capable of providing specialized support in the design, production, and evaluation of mRNA formulation services. Our mRNA manufacturing template gives a robust workflow, while our lipid nanoparticle (LNP) manufacturing processes ensure a high-quality and consistent supply. 

We provide high throughput evaluations along with faster results. In addition to that, we provide many different mRNA formulation services to meet your various end-point in vaccine delivery. These formulations come with specific functionality to improve the efficiency of vaccines in the physiological environment.

Applications

1.mRNA-based cell therapy

Cell therapy utilizes “trained” immune cells to attack the disease in the patient. The vastly well-known use of this method is Chimeric Antigen Receptor T-cell (CAR-T). T-cell progenitors are isolated directly from the victim for use in therapy. Via in vitro translated mRNA, T cells are made to express chimeric antigen receptors that target a particular protein expressed by the patient’s cancer. When CAR-T cells are injected into the patient they will attack the cancer cells, facilitating patient survival.

2. mRNA based vaccines

An effective vaccine will drive an immune response that directs to antigen-specific B and T cells without triggering a dangerous infection. Vaccines mimic infection by exposing the body to antigens existing in the target infectious agent. While traditional vaccines employ the actual pathogen in a live attenuated, inactivated, or subunit format, antigen introduction by mRNA vaccines has recently gained popularity for its rapid development timelines and lower risk. mRNA is utilized to express pathogen-associated epitopes, enabling the immune system to mount a response and form memory.

3.mRNAs in replacement therapy

Many human diseases result from an absence of a specific protein or a reduction in its function. Therapeutic delivery of mRNA encoding the impacted protein can restore or bolster the process to healthy levels. This method gives benefits compared to traditional protein therapy, involving longevity of treatment and natively processed protein.  While protein therapy can be utilized to replace secreted proteins, mRNA therapy can replace intracellular and transmembrane proteins, expanding the spectrum of diseases that can be treated.

4.mRNAs for tissue regeneration 

mRNA therapeutics could illustrate the next-generation drug for tissue restoration in regenerative medicine. Non-immunogenic mRNA can be generated with the aim of modified nucleosides. Modification of the mRNA structure facilitates the synthesis of stable, non-immunogenic in vitro transcribed mRNA.

5.mRNAs for cancer immunotherapy

Synthetic mRNA gives a template for the synthesis of any given protein, protein fragment or peptide and lends itself to a wide range of pharmaceutical applications, including various modalities of cancer immunotherapy. With the ease of rapid, big-scale Good Manufacturing Practice-grade mRNA production, mRNA is ideally poised not only for off-the-shelf cancer vaccines but also for personalized neoantigen vaccination. The potential to stimulate pattern recognition receptors and hence an anti-viral type of innate immune response equips mRNA-based vaccines with inherent adjuvanticity. Nucleoside modification and elimination of double-stranded RNA can lessen the immunomodulatory activity of mRNA and increase and prolong protein production.

6.Allergy tolarization with mRNA therapeutics

mRNA vaccines open the field for a safety-optimized prophylactic vaccination against allergic disorders. Future research concerning long-term effects and vaccine-induced versus natural immune responses will be desired to transfer this knowledge to the clinics.

Conventional as well as self-replicating mRNA vaccines have indicated their potential to prevent the induction of an allergic phenotype in terms of allergen-specific IgE, allergy-associated cytokine profiles, eosinophilic lung infiltration, and airway hyperreactivity.

7.mRNA for genome engineering 

Quick and transient expression of in vitro transcribed mRNA (IVT mRNA) in target cells is a current main challenge in genome engineering therapy. To enhance mRNA delivery efficiency, a series of amphiphilic polyaspartamide derivatives were synthesized to contain several hydrophobic moieties with cationic diethylenetriamine (DET) moieties in the side chain and systematically compared as mRNA delivery vehicles (or mRNA-loaded polyplexes). The obtained outcomes indicated that the side chain structures of polyaspartamide derivatives were crucial for the mRNA delivery efficiency of polyplexes. 

8.Genetic reprogramming of cell and tissue with mRNA

mRNA reprogramming is the greatly unambiguously “footprint-free,” most productive, and perhaps the best fitted to clinical production of stem cells. 

The discovery that ordinary skin cells can be turned into pluripotent stem cells by the forced expression of specified factors has raised hopes that personalized regenerative treatments based on immunologically compatible material originating from a patient’s cells might be understood in the not-too-distant future. A major barrier to the clinical use of induced pluripotent stem cells (iPSCs) was originally presented by the need to employ integrating viral vectors to express the factors that induce an embryonic gene expression profile, which includes potentially oncogenic change of the normal genome. Various “non-integrating” reprogramming systems have been formulated over the last decade to address this problem.

9.Infectious Diseases 

mRNA vaccines against infectious diseases could be formulated as prophylactic or therapeutic. mRNA vaccines expressing antigens of infectious pathogens induce both strong and potent T cell and humoral immune responses.

10.Cancer

mRNA is an outstanding approach for targeted therapies. Generation of mRNA is rapid compared to traditional therapeutics, and can be easily tailored to express a specific target protein or epitope. For personalized cancer vaccines, mRNA is utilized to express tumor-associated epitopes (neoantigens) in host cells. Once presented by the cell, the victim’s own immune system will recognize the antigen and mount a response against the cancer.

11.Genetic disorders 

Genetic defects are corrected by the introduction of specific DNA sequences into the genome, mRNA-based therapy promises new improvements in the treatment of single-gene diseases.

12.mRNA for stem cell differentiation 

mRNA can be utilized for reprogramming (dedifferentiation) of somatic cells to stem cells or directed differentiation of stem cells to the desired cell type. In addition, somatic cells can be directly reprogrammed to a various somatic cell type (trans‐differentiation) utilizing mRNAs.

References

1.Qiu, P. et al. Gene gun delivery of mRNA in situ results in efficient transgene expression and genetic immunization. Gene Ther. 3, 262–268 (1996).

2.Wolff, J. A. et al. Direct gene transfer into mouse muscle in vivo. Science 247, 1465–1468 (1990).

3.Hoerr, I. et al. In vivo application of RNA leads to induction of specific cytotoxic T lymphocytes and antibodies. Eur. J. Immunol. 30, 1–7 (2000).

4.Mitchell, D. A. et al. Selective modification of antigen-specific T cells by RNA electroporation. Hum. Gene Ther. 19, 511–521 (2008).

5.Zangi, L. et al. Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nature Biotech. 31, 898–907 (2013).

6.Rabinovich, P. M. et al. Synthetic messenger RNA as a tool for gene therapy. Hum. Gene Ther. 17, 1027–1035 (2006).