mRNA is a versatile tool that can be used for therapeutic protein replacement, gene editing, cell therapy, vaccines, and more. Nearly any protein can be introduced via mRNA, enabling cellular expression of gene editing tools or antigens as needed. Sequence engineering and chemical modifications such as modified nucleoside triphosphates (NTPs) used during in vitro transcription offer precise control mechanisms for mRNA performance. With rapid development timelines and scalable manufacturing, mRNA is an attractive solution for numerous therapeutic applications.
Current mRNA therapeutics function either via direct, in vivo introduction of mRNA into the patient or by ex vivo use of mRNA to modify cells which are then injected. When mRNA is introduced directly it is packaged into a delivery vessel, such as lipid nanoparticles (LNPs), to facilitate its successful uptake into host cells. Organ-targeting delivery methods are an ongoing area of mRNA research.
Cell therapy uses “trained” immune cells to attack disease in the patient. The most well-known use of this approach is Chimeric Antigen Receptor T Cells (CAR-T). T cell progenitors are isolated directly from the patient for use in the therapy. Via in vitro translated mRNA, T cells are made to express chimeric antigen receptors that target a specific protein expressed by the patient’s cancer. When CAR-T cells are injected into the patient they will attack the cancer cells, promoting patient survival.
mRNA can be used to introduce non-native proteins into cells, including tools for gene editing such as the CRISPR-Cas family of nucleases. This enables scientists to quickly and inexpensively make targeted genomic changes in living cells. Variants on this technology such as DNA Base Editors offer improved precision of gene editing.
Many human diseases are caused by an absence of a specific protein or a reduction in its function. Therapeutic delivery of mRNA encoding the impacted protein can restore or bolster function to healthy levels. This method offers advantages compared to traditional protein therapy, including longevity of treatment and natively processed protein. While protein therapy can be used to replace secreted proteins, mRNA therapy can replace intracellular and transmembrane proteins, broadening the spectrum of diseases that can be treated.
Antibody therapy has traditionally entailed the infusion of monoclonal antibodies produced by hybridomas. However, the high costs and supply chain challenges of manufacturing biologics have impeded access to these therapies. The scalability and relatively low expense of mRNA manufacturing make mRNA antibody therapy an attractive alternative. Additionally, administering an mRNA transcript that encodes for an antibody enables prolonged patient expression of the therapeutic, rather than the very limited duration of protein therapy.
mRNA is an excellent approach for targeted therapies. Production 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 used to express tumor-associated epitopes (neoantigens) in host cells. Once presented by the cell, the patient’s own immune system will recognize the antigen and mount a response against the cancer.
An effective vaccine will drive an immune response that leads to antigen-specific B and T cells without triggering a dangerous infection. Vaccines mimic an infection by exposing the body to antigens present in the target infectious agent. While traditional vaccines utilize 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 used to express pathogen-associated epitopes, enabling the immune system to mount a response and form memory.
Self-amplifying mRNA (SAM) vaccines are a variant of mRNA vaccine technology. SAM vaccines utilize alphavirus genetic replication machinery to amplify the mRNA message within the cell, meaning that lower dosing is required to produce the same expression level. The mRNA manufacturing process can be optimized for self-amplifying mRNA with reagents like CleanCap® AU.
During a pandemic like Covid-19, rapid vaccine development and manufacturing is critical. Once the pathogen’s sequence is known, mRNA vaccine candidates can quickly be designed and tested. mRNA manufacturing platforms function consistently regardless of sequence, which streamlines process development and enables rapid scale-up of manufacturing.