New RNA Switch Could Make Gene Therapies Safer and More Controllable

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• Liezel Labios - [email protected]

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• Gene Therapy

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Bioengineers at the University of California San Diego have developed a technology that allows drugs to control when cells produce therapeutic proteins, which could potentially make gene therapies safer and more adaptable for treating chronic diseases.

The technology could help address a longstanding challenge in gene therapy: how to provide long-lasting treatment without allowing therapeutic proteins to remain active at potentially harmful levels. In preclinical studies, researchers used the approach to activate production of a protein that helped reverse obesity and fat buildup in the liver.

The findings were published in Molecular Cell.

Gene therapies work by delivering genetic instructions that tell cells to make a therapeutic protein. But once those instructions are delivered, it can be difficult to control how much protein cells produce and for how long. Some proteins are beneficial only within a narrow range. Too little may not treat the disease, while too much or prolonged exposure can cause harmful side effects.

To achieve greater control, researchers in the lab of Prashant Mali, professor in the Shu Chien-Gene Lay Department of Bioengineering at the UC San Diego Jacobs School of Engineering, developed what they call adaptamers (short for ADAR-modulatable aptamers). These are short pieces of RNA that use small-molecule drugs to regulate protein production. When a drug binds to an adaptamer, it activates a natural cellular process that allows cells to read genetic instructions and produce the desired protein.

The adaptamer system offers a way to activate protein production, as well as reduce it without having to remove the gene therapy itself. Drug exposure and concentration can influence how strongly the switch is activated. Meanwhile, removing the activating drug allows protein production to decline. This raises the possibility of adjusting protein production through drug dosing, although further research is needed to establish how precisely protein levels can be controlled.

A drug-controlled gene therapy could potentially give clinicians a way to adjust treatment as a patient's needs change, explained study first author Jack Bryant, a bioengineering Ph.D. student in Mali's research group. "They could increase the dose of the drug to the point where the desired therapeutic effect is seen, then reduce the dose or stop giving the patient the drug if protein levels become too high, side effects emerge, or the gene therapy is no longer needed."

To demonstrate the technology's therapeutic potential, the team engineered adaptamers to produce a protein called FGF21 - which helps regulate metabolism and has shown promise for treating obesity - using a small molecule drug such as tetracycline or doxycycline. Although FGF21 can promote weight loss and improve metabolic health, excessive or prolonged exposure can contribute to muscle loss and reduced bone density.

Preclinical studies showed that activating FG21 production led to substantial weight loss, improved blood sugar regulation and a near-complete reversal of fat buildup in the liver.

Next steps include refining the system to enable gene therapies for the brain that can be switched on and off as needed, and safer ways to deliver molecules that help tissue repair itself.

Full study: "Regulatable in vivo gene expression via adaptamers." Co-authors include Laura Herron, Yesh Doctor, Finn McRae, Jocelyn Wang, Theodore Hirsh, Andrew Portell and Satheesh Kumar, all at the Shu Chien-Gene Lay Department of Bioengineering at UC San Diego.

This work was supported by the U.S. National Institutes of Health (grants R01HG012351, R01CA310063, and R01NS131560), the California Institute for Regenerative Medicine (CIRM grant DISC4-19271), the U.S. Department of Defense (grant W81XWH-22-1-0401) and UC San Diego Institutional Funds.

Disclosures: The authors have filed a patent based on this work. Prashant Mali is a scientific co-founder of Shape Therapeutics, Boundless Biosciences, Navega Therapeutics, Pi Bio, and Engine Biosciences. The terms of these arrangements have been reviewed and approved by the University of California San Diego in accordance with its conflict-of-interest policies.

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