mRNA APPLICATIONS
Therapeutic Applications for mRNA
Scientists have looked at using mRNA for therapies for a long time. Because mRNA can be used to make any protein in the cell, it can be, theoretically, used to do (fix) almost anything in a cell. While some practicalities limit what it will likely be used for, mRNA has the potential to be useful in many ways. Add to that its rapid development timelines and scalable manufacturing, and it’s clear why mRNA is an attractive solution for numerous therapeutic applications.
One way to categorize mRNA-based therapeutic strategies is according to whether the mRNA is introduced to the cell inside a person (in vivo) or to a cell outside of the person and in a lab (ex vivo). Different therapeutic approaches can use either, both, or a combination of these delivery methods.
When mRNA is introduced to a cell in vivo, it must be packaged into a delivery vessel (like a shipping box; these are often lipid nanoparticles). The “box” helps prevent the mRNA from breaking down before it reaches the correct cell, and it facilitates mRNA entry into a cell. When mRNA is introduced to a cell in a lab, aka ex vivo, there are a variety of different methods scientists can use to get the mRNA into the cell of interest. Often, the cell of interest has been taken from a biopsy or blood draw from a patient. After the mRNA enters the cells in a lab, it changes (fixes) something about the cells and then those cells are re-introduced into a patient as the treatment.
A major current challenge for mRNA therapeutics is getting the mRNA to the right cell in the patient. This “delivery” problem is an ongoing area of mRNA research for both in vivo and ex vivo applications. The range of diseases these mRNA applications could treat is vast, spanning oncology, genetic/rare diseases, autoimmune, and infectious diseases.
mRNA VACCINES
mRNA vaccines have recently gained popularity through the COVID-19 pandemic for their rapid development timelines and lower safety risk. Generally speaking, vaccines mimic infection by exposing the body to small parts of a particular infectious agent, most often a virus. An effective vaccine will induce an immune response in the body that prepares it to fight the real pathogen, without triggering a dangerous infection. While traditional vaccines use a modified form of the actual pathogen, mRNA vaccines express pathogen-associated epitopes, but both can enable the immune system to mount a response and form immune memory.
SELF-AMPLIFYING mRNA VACCINES
Self-amplifying RNA (saRNA) vaccines are a variant of mRNA vaccine technology. saRNA vaccines are built so they can (safely) amplify themselves within the cell, meaning that a lower dose can produce the same therapeutic effect. A lower dose simplifies manufacturing and delivery processes—in other words, more vaccine can be made available more easily. A limited number of saRNA vaccines have reached clinical trials so far.
PANDEMIC RESPONSE
During the COVID-19 pandemic, the world learned that rapid vaccine development and manufacturing is critical. Once the pathogen’s genome is sequenced, mRNA vaccine candidates can quickly be designed and tested. mRNA manufacturing platforms function consistently regardless of sequence, streamlining process development and enabling rapid manufacturing scale. These advantages are key when time is of the essence.
PERSONALIZED CANCER VACCINES
mRNA is an excellent approach for personalized medicine or targeted therapies that are common in oncology. In these sorts of therapies, the drug is designed for a specific patient, or a specific genetic change in a patient’s cancer. Production of mRNA is quick compared with traditional therapeutics and can be easily tailored to express a precise target—two key characteristics necessary for this application. When the mRNA vaccine is given to the patient, it activates their immune system to recognize the cancer cells and kill them.
Select Publications to Learn More
Medina-Magües LG, et al. mRNA Vaccine Protects against Zika Virus. Vaccines (Basel) 2021; 9(12):1464.
Pascolo S. Vaccines against COVID-19: Priority to mRNA-Based Formulations. Cells 2021; 10(10):2716.
Sajid A, et al. mRNA vaccination induces tick resistance and prevents transmission of the Lyme disease agent. Sci Transl Med 2021;13(620).
GENE EDITING
mRNA can also be used to introduce proteins into cells that are defectively not there. Importantly, this can include the tools needed for gene editing strategies such as the CRISPR-Cas family of nucleases. The CRISPR technique allows scientists to make changes quickly and cost-effectively to the DNA in living cells. mRNA is an important component to a highly effective CRISPR system. Variants of this technology, such as DNA Base Editors, offer improved precision of gene editing. The precision of these strategies in vivo is still being evaluated, but gene editing technologies hold the potential to cure diseases with a one-time DNA edit.
Select Publications to Learn More
Nelson JW, et al. Engineered pegRNAs improve prime editing efficiency. Nat Biotechnol 2022; 40(3):402–410.
Anzalone AV, et al. Programmable deletion, replacement, integration and inversion of large DNA sequences with twin prime editing. Nat Biotechnol 2022; 40(5):731–740.
Kenjo E, et al. Low immunogenicity of LNP allows repeated administrations of CRISPR-Cas9 mRNA into skeletal muscle in mice. Nat Commun 2021; 12(1):7101.
Packer MS, et al. Evaluation of cytosine base editing and adenine base editing as a potential treatment for alpha-1 antitrypsin deficiency. Mol Ther 2022; 30(4):1396–1406.
CELL THERAPY
Cell therapy uses the ex vivo approach described above to “train” a patient’s own immune cells to attack their disease. The most well-known use of this approach is chimeric antigen receptor T cells (CAR T) in cancer therapy. T-cell progenitors are isolated from the patient, altered in the lab (mRNA is added to them), then the cells are re-introduced into the patient as therapy. The mRNA that is added makes the T cells 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 attack the cancer cells, promoting patient survival.
Select Publications to Learn More
Chabanovska O, et al. mRNA – A game changer in regenerative medicine, cell-based therapy and reprogramming strategies. Adv Drug Deliv Rev 2021; 179:114002.
Parayath NN, et al. In vitro-transcribed antigen receptor mRNA nanocarriers for transient expression in circulating T cells in vivo. Nat Commun 2020; 11(1):6080.
Billingsley MM, et al. Ionizable Lipid Nanoparticle-Mediated mRNA Delivery for Human CAR T Cell Engineering. Nano Lett 2020; 20(3):1578–1589.
PROTEIN REPLACEMENT
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 with traditional protein therapy, including longevity of treatment and natively processed protein. Although protein therapy is best used to replace secreted proteins, mRNA therapy can replace intracellular and transmembrane proteins, broadening the spectrum of diseases that can be treated.
Select Publications to Learn More
Swingle KL, et al. Amniotic fluid stabilized lipid nanoparticles for in utero intra-amniotic mRNA delivery. J Control Release 2022; 341:616–633.
Qiu Y, et al. Effective mRNA pulmonary delivery by dry powder formulation of PEGylated synthetic KL4 peptide. J Control Release 2019; 314:102–115.
ANTIBODIES
Antibody therapy refers to treating a patient with antibodies (made ex vivo) to bolster or provide new antibodies to fight an infectious disease, toxin, or cancer. It has traditionally entailed the infusion of monoclonal antibodies produced by hybridomas, which is a fusion of specific cell types made to produce large numbers of one specific antibody. However, the high costs and supply chain challenges of manufacturing antibodies have impeded access to these therapies. Instead, administering an mRNA transcript that encodes an antibody enables the prolonged expression of the therapeutic compared with traditional protein therapy. The scalability and relatively low expense of mRNA manufacturing make mRNA-encoded antibody therapy an attractive alternative. Antibody therapies apply to a wide range of indications, and so they further broaden the potential scope of mRNA therapeutic applications.
Select Publications to Learn More
Hao S, et al. BiTE secretion from in situ-programmed myeloid cells results in tumor-retained pharmacology. J Control Release 2022; 342:14–25.
Therapeutic Applications for mRNA
mRNA can be used in many therapeutic applications. One way to categorize these uses is whether the mRNA is added to the cell of interest in a lab (ex vivo) or directly in the patient (in vivo). There are a wide range of disease areas for which mRNA therapeutics could be effective.
mRNA APPLICATION
ex vivo / In vivo
Therapeutic area
Vaccines
mRNA vaccines
Cancer vaccines
SAM vaccines
In vivo
Infectious diseases
Oncology
mRNA replacement
In vivo
Genetic diseases
Rare diseases
Oncology
Gene editing
Ex vivo / In vivo
Genetic diseases
Rare diseases
Cell therapies
Ex vivo
Oncology
Antibodies
Ex vivo
Oncology
Infectious diseases
Therapeutic Applications for mRNA
mRNA can be used in many therapeutic applications. One way to categorize these uses is whether the mRNA is added to the cell of interest in a lab (ex vivo) or directly in the patient (in vivo). There are a wide range of disease areas for which mRNA therapeutics could be effective.
mRNA Applications Webinars
Oct 28, 2022
Stealth Mission: Novel mRNA Vaccine Delivery System