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The decoding process by which any cell within the body translates our genetic material, DNA, into functional proteins to carry out important biological tasks, is known as translation1.
Beginning with a process called transcription, the genetic information of the DNA present in the nucleus, is transferred to a messenger RNA (mRNA) molecule.
The mRNA molecule is then transferred into the cytoplasm where its nucleotide sequence is used by the ribosomes to synthesize polypeptide chains which are folded into protein molecules1. Since the discovery of this protein synthesis process has occurred, Researchers have spent a considerable amount of time understanding its complexity, as well as looking at how this process could be applied to therapeutic applications.
By injecting an appropriate mRNA sequence into the cell, any target protein of interest can be synthesized using the cell machinery. The use of mRNA for therapeutics has been investigated widely for the treatment of cancer as well as for the development of vaccines for various diseases2.
Even though there are a myriad of potential applications for mRNA in therapeutics, only a small fraction of the mRNA delivered results in protein translation due to the following reasons. First, the mRNA introduced into the cell needs to find a ribosome in the busy cytoplasm environment, second, the enzyme present in the cytoplasm can degrade the mRNA, third, the cells may lack enough poly-A protein for translation of the additional mRNA introduced into them2.
Therefore, an effective technique that delivers mRNA efficiently would serve a great deal in treating various diseases as well as delivering vaccines.
A recent study published in the international journal, Angewandte Chemie, by Dr. Paula Hammond’s team from the Massachusetts Institute of Technology (MIT)’s Department of Chemical Engineering has demonstrated a new method for the efficient delivery of mRNA into the cells2.
In their previous research, the team of Researchers successfully attached a protein cap to one end of the mRNA sequence, which is necessary for the translation process2,3. In the current study, the MIT team manipulated the other end of the mRNA sequence by adding a poly-A binding protein to the other end of the mRNA which helps in the mRNA to bind to the translational machinery, the ribosomes2.
Cells do not allow charged substances to cross the plasma membrane, therefore it will be difficult for the negatively charged mRNA sequence to enter the cells2,3. To neutralize the charge, Hammond’s team coated the complex with a polymer composed of a modified polypeptide sequence strung like a chain. By serving as a scaffold, this polymer coating also helps in holding the mRNA and the poly-A binding protein in close contact2.
Once this mRNA enters the cell, the poly-A binding protein helps in preventing enzymatic degradation and aids in finding the ribosome for protein translation. The mRNA then forms a closed loop, allowing for the ribosome to translate the nucleotide sequence into protein several times, resulting in several copies of proteins2.
Hammond’s team from MIT demonstrated this by delivering an mRNA sequence that encodes for a glowing protein, luciferase into mouse lungs. Due to the positive charge on the polypeptide, the mRNAs were able to be bound to the red blood cells (RBC), and eventually delivered to lungs where they are translated into luciferase protein2.
Because the mRNA sequences were pre-assembled to mimic the structure of protein synthesis, a four-fold increase in the luciferase protein was achieved as compared to conventional methods, which usually have very low yields2,3.
Because there is no change in the genetic information, this new method has a high safety factor2. The research team is now trying to tweak the structure of the mRNA to direct the mRNA molecules to specific target cells like tumor cells, which can potentially revolutionize the therapeutic applications of mRNA for treating diseases such as cancer, as well serve as a great approach for the delivery of vaccines2.
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References:
- “Translation: DNA to mRNA to Protein” S. Clancy & W. Brown. Nature Education. (2008).
- “Polyamine-Mediated Stoichiometric Assembly of Ribonucleoproteins for Enhanced mRNA Delivery” J. Li, Y. He, et al. Angewandte Chemie. (2017). DOI: 10.1002/anie.201707466.
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