Protein Replacement Therapy
In 1992, the preclinical evaluation of in vitro-transcribed (IVT) mRNA for supplementing a physiological protein was first reported. Much effort has been made on studying IVT mRNAs since the report, thus opening the therapeutic application of IVT mRNA for protein replacement. Since intracellular delivery of mRNAs theoretically can express various types of proteins inside the host cells, the mRNA-based drug method holds the potential to be employed in a broad range of diseases. Based on the development of technology, the in vivo-translational potential of IVT mRNA has been demonstrated by multiple preclinical studies. Several proteins have been administrated by the mRNA-based drug method.
mRNA-based protein replacement therapy
As powerful biotherapeutics, proteins have been used to deal with a broad range of diseases via their remarkable ability to regulate various biological processes. However, to support this therapy, a substantial financial investment (e.g., production costs and product maintenance costs) is required. The large-scale production of protein therapeutic drugs demands complicated facilities and verification steps. In addition, to maintain their protein structure and function, the drugs need to be stored under strictly controlled storage conditions before administration. Therefore, IVT mRNA has been utilized as a novel approach for protein replacement to address these problems and received much attention.
Compared with the traditional administration of protein drugs to the body, the mRNA-based protein replacement therapy is based on supplementing desired proteins inside the target cells, which is more effective. In other words, the cell in the body is like a biological factory that can directly express high quality proteins without complicated production facilities and quality control steps. As a novel method for the field of protein replacement, the mRNA-based protein replacement therapy has superior features, including,
- Have the capability to express virtually any desired protein inside the host cells
- Low risk of insertional mutagenesis
- Transient production of the encoded protein
- Economic production and low development cost
The administration of mRNA-based protein replacement therapy
With the advancements of mRNA optimization and improved mRNA purification protocols, protein supplementation has become the most obvious application for mRNA-based drugs. Before administration, the design of mRNAs that express therapeutic proteins should comply with the principles of low immunogenicity, prolonged stability, and potent translation. To sustain therapeutic protein levels, repeated administrations of mRNA-based drugs are performed. And the dosing frequency is determined by the activity of the protein, its half-life, the types of target cells as well as administration routes.
The application of mRNA-based protein replacement therapy
At present, most mRNA-based protein replacement therapies are toward the heart, liver, and lungs due to the accessibility of these organs. More efficient delivery strategies, such as novel biomaterials and different administration methods, are required for other cells and tissues. Since the therapeutic mRNA can express various types of proteins, including the missing or infra-expressed proteins, the main applications of mRNA-based protein replacement therapy are genetic and rare diseases. Besides, it can express foreign proteins and be used in other disease conditions uncorrelated with a genomic defect.
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- Gómez-Aguado, I.,et al. (2020). "Nanomedicines to Deliver mRNA: State of the Art and Future Perspectives." Nanomaterials, 10(2), 364.
- Kwon, H., et al. (2018). "Emergence of synthetic mRNA: In vitro synthesis of mRNA and its applications in regenerative medicine". Biomaterials, 156, 172-193.