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New approach for mRNA delivery

New technique could make it easier to deliver mRNA into cells to treat disease or deliver vaccines....


By delivering strands of genetic material known as messenger RNA (mRNA) into cells, researchers can induce those cells to produce any protein encoded by that mRNA. Even though achieving efficient delivery of mRNA is challenging, this technique holds great potential for administering vaccines or treating diseases such as cancer.
A team of MIT chemical engineers, inspired by the way that cells translate their own mRNA into proteins, has now designed a synthetic delivery system that is four times more effective than delivering mRNA on its own.

"If we want to be able to deliver mRNA, then we need a mechanism to be more effective at it because everything that's been used so far gives you a very small fraction of what would be optimal," says Paula Hammond, a David H. Koch Professor in Engineering, the head of Massachusetts Institute of Technology (MIT), Department of Chemical Engineering, and a member of MIT's Koch Institute for Integrative Cancer Research. She is also the senior author of the paper, which appears in Angewandte Chemie.
Messenger RNA carries genetic instructions from DNA which cannot leave the cell nucleus to the cell's ribosomes, which assemble proteins based on that mRNA sequence.

Messenger RNA is appealing as a potential vehicle to treat disease or deliver vaccines because after an mRNA strand is translated into the desired protein, it eventually degrades.

"It doesn't change the genetic code," Hammond says. "There's no chance that incorporation of a gene might happen, so the safety factor is a lot higher."

For this approach to work, mRNA has to get into cells to reach the ribosomes and be translated into protein. In a previous study, MIT researchers found they improved mRNA translation by attaching a protein cap to one end of the mRNA strand. This cap helps mRNA form a complex that initiates translation.
In the new study, researchers focused on the other end of the mRNA molecule. mRNA usually has a long, naturally occurring "poly-A tail," made up of a long sequence of adenosine repeats. Adenosine stabilizes mRNA and helps it resist being broken down by enzymes within the cell.

The MIT team attached a protein called a poly-A binding protein to that poly-A tail. This protein, found naturally in cells, helps mRNA bind to ribosomes and thus begin translation. Then they coated this complex with a polymer known as a polypeptide, a sequence of modified amino acids strung together making a chain. This polypeptide chain acts as a scaffold holding poly-A binding protein in close contact with mRNA, helping to neutralize its negative charge. Without neutralization, mRNA would not be able to pass through cell membranes, which are also negatively charged.
Once the polymer-coated mRNA enters a cell, the poly-A binding protein protects it from braking down and helps it link with ribosomes. The mRNA forms a closed loop so that a ribosome can cycle through it many times, producing many copies of the target protein. In this way, the effect of mRNA, which is a very costly genetic therapy, can be significantly enhanced by combination with cheaper synthetic polypeptides and proteins.

ribisome


Ribosomes which translate mRNA, are the purple dots lining the walls of the Rough Endoplasmic Reticulum attached to the cell nucleus.
"The conventional approach is just to deliver mRNA into the cells," Li explains. "But once mRNA gets into cells it might be degraded, so we form a complex which is crucial for initiation of mRNA translation." Researchers tested this system by delivering mRNA that encodes the gene for luciferase, a glowing protein, into the lungs of mice.
They found with this type of delivery, cells produced four times as much protein as they did when only mRNA was packaged with the same polypeptide.

One reason this system is more efficient, the researchers believe, is that it eliminates the need for mRNA to find poly-A binding proteins in the crowded cytoplasm environment after the mRNA enters the cell.

"We realized that cells probably only make enough of this poly-A binding protein to translate their own mRNA," He says. "Once you deliver excess mRNA, the cell does not have enough of this helper protein to translate it. We realized that we need to give it more helper protein, pre-assemble it with our polypeptides to mimic the structure of protein synthesis, then co-deliver this bio-inspired assembly into the cell."
In this study, the mRNA particles accumulated in the lungs because of the positive charge from the polypeptide. That charge allowed the particles to attach to red blood cells and catch a ride to the lungs.

Now researchers plan to modify particles with polymers that will direct them to other locations in the body, including tumors.

The team is also working on improving stability in polypeptide molecules by adding a hydrophobic tail to one end, and by attaching a polymer called PEG. Both of these modifications should help mRNA particles circulate longer in the body, allowing them to reach their intended destinations.

Abstract
Messenger RNA (mRNA) represents a promising class of nucleic acid drugs. Although numerous carriers have been developed for mRNA delivery, the inefficient mRNA expression inside cells remains a major challenge. Inspired by the dependence of mRNA on 3?-terminal polyadenosine nucleotides (poly A) and poly A binding proteins (PABPs) for optimal expression, we complexed synthetic mRNA containing a poly A tail with PABPs in a stoichiometric manner and stabilized the ribonucleoproteins (RNPs) with a family of polypeptides bearing different arrangements of cationic side groups. We found that the molecular structure of these polypeptides modulates the degree of PABP-mediated enhancement of mRNA expression. This strategy elicits an up to 20-fold increase in mRNA expression in vitro and an approximately fourfold increase in mice. These findings suggest a set of new design principles for gene delivery by the synergistic co-assembly of mRNA with helper proteins.

All authors: Jiahe Li, Yanpu He, Wade Wang, Connie Wu, Celestine Hong, Paula T. Hammond.

The research was funded by the Department of Defense (DoD) Ovarian Cancer Research Program Teal Innovator Award, the DoD Peer Reviewed Orthopaedic Research Program Idea Development Award, and a Koch Institute Quinquennial Postdoctoral Fellowship.

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Sep 26, 2017   Fetal Timeline   Maternal Timeline   News   News Archive




Polyamine-Mediated Stoichiometric Assembly of Ribonucleoproteins for Enhanced mRNA Delivery. Image Credit: Hammond, Massachusetts Institute of Technology (MIT)



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