Gene-based therapies poised for major upgrade thanks to Oregon State University research

(Press-News.org) PORTLAND, Ore. – Drug delivery researchers have vastly improved the potential of genetic therapies by overcoming the challenge of consistently getting genes and gene-editing tools where they need to be within cells.

Findings of the study spearheaded by Oregon State University College of Pharmacy graduate student Antony Jozić were published today in Nature Biotechnology.

When gene therapies enter a cell, they are often sent to lysosomes, the cell’s trash and recycling centers, where therapeutic genetic material is broken down before it can work. For gene therapies to succeed, they must avoid disposal and reach the part of the cell where they can function. 

Jozić, under the guidance of Gaurav Sahay, professor of pharmaceutical sciences, led the hands-on work that made it possible to rapidly measure, for the first time in living organisms, which gene-carrying nanoparticles avoid destruction and which are discarded.

“Once you can measure something, you can design around it,” Sahay said. “Designs based on our measurements allow for new lipid nanoparticles capable of much more efficient delivery.”

Lipids are fatty acids and similar organic compounds including many natural oils and waxes, and nanoparticles are tiny pieces of material ranging in size from one- to 100-billionths of a meter.

Sahay, Jozić and scientists at OHSU, Tennessee Technological University, Yeungnam University in South Korea, and the University of Brest in France developed a DNA-based barcoding test that showed, in mouse models, how much of the genetic material carried by lipid nanoparticles ended up as refuse versus how much successfully reached its target.

“That allowed us to quantify how efficiently different nanoparticle designs release their cargo,” Jozić said. “It was a huge outcome for us and a particularly meaningful one for me after working on this for several years.”

A key component of lipid nanoparticles is a lipid that’s ionizable – able to change its charge state depending on the acidity of its surroundings. Ionizable lipids help both in the packing of genetic material and in interacting favorably with cellular membranes.

Guided by the measurements enabled by the barcoding system, the researchers identified and validated a new class of lipid nanoparticles built around improved ionizable lipid systems. The new particles safely enabled powerful gene editing at much lower doses than current advanced delivery methods.

“The study also clearly demonstrated that the main problem with gene therapies is getting the cargo to the right part of the cell once it’s inside,” Sahay said. “This insight resolves a longstanding challenge in our field, to track genetic material inside the subcellular compartments within the cell in a living organism, and provides a road map for improving RNA and gene-editing medicines and reducing off-target effects.”

The National Institutes of Health, the Defense Advanced Research Projects Agency and the M.J. Murdock Charitable Trust supported the research, which also included OSU’s Deepak Sahel, Emily Bodi, Michelle Palumbo, Aishwarya Vasudevan, Namratha Murthy, Yulia Eygeris, Milan Gautam and Elissa Bloom.

Sahay said publication in Nature Biotechnology strongly validates the drug delivery science being developed within OSU’s collaborative research environment.

“This game-changing work really highlights our growing leadership in this space and our ability to attract and train outstanding students,” he said. “By working together from the earliest design stages with our collaborators in France, Paul-Alain Jaffrès and his graduate student Chole Le Roux, we created some of the most potent ionizable lipids reported to date that deliver gene-editing tools far more efficiently than existing systems.”

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