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Stanford University School of Medicine

Mice glowing like fireflies show that new gene therapy process has promise

Glowing thighs were reason for a celebration recently among Stanford researchers working on a new process for gene therapy. Through a collaborative effort led by Christopher Contag, PhD, professor of pediatrics and of microbiology and immunology; Robert Waymouth, PhD, professor of chemistry; and Paul Wender, PhD, professor of chemistry, the researchers developed a new way to deliver a type of RNA into cells to instruct the creation of proteins.

Their technique, detailed in a paper in Proceedings of the National Academy of Sciences, led to successful expression in mice of the proteins that make a firefly glow and may bring us one step closer to the creation of individualized therapeutics from a person’s own cells.

Waymouth, in a Stanford press release, characterized their excitement:

It’s almost a childlike enthusiasm we have for this. The code for an insect protein is put into an animal and that protein is not only synthesized in the cells but it’s folded and it becomes fully functional, capable of emitting light.

Accomplishing this feat involved two distinct challenges: getting a type of RNA called mRNA from a firefly into a mouse’s cells and giving it the freedom to create proteins once inside. Already, the researchers knew that positively charged transport molecules, polycations, can carry mRNA, which is negatively charged, across the cell membrane. The problem with past attempts to use polycations is they don’t let go of the mRNA after the crossing, limiting its ability to lead to protein production.

The Stanford technique, called charge-altering releasable transporters (CARTs), avoids this issue with a clever transformation, explained Wender:

What distinguishes this polycation approach from the others, which often fail, is the others don’t change from polycations to anything else. Whereas, the ones that we’re working with will change from polycations to neutral small molecules. That mechanism is really unprecedented.

The change to neutral small molecules means their creation biodegrades inside the cell, detaches from the mRNA, and is eventually excreted from the body. This, along with the fact that mRNA’s effects are temporary, makes this technique especially appealing for vaccination, where it could instruct our bodies to put up an immune response and then dissolve, leaving no trace of foreign materials. The researchers are also hoping to apply CARTs to another genetic messenger that could lead to more permanent effects.

Previously: Stanford researcher details structure of sugar transporter called SWEET and Special delivery: Discovery of viral receptor bodes better gene therapy
Photo by L.A. Cicero

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