Kit S. Lam, distinguished professor and chair of the Department of Biochemistry and Molecular Medicine in the School of Medicine, and R. Holland Cheng, professor of Molecular and Cellular Biology in the College of Biological Sciences, aim to demonstrate that CRISPR, a technology that allows alteration of DNA sequences to modify gene function, can be successfully packaged and delivered to target cells in a living animal.

The award is the second major CRISPR grant at UC Davis as part of the NIH Somatic Cell Genome Editing Consortium (SCGE). In May, UC Davis announced the launch of an NIH-funded research center dedicated to helping the nation develop safe and effective genome editing. The $9 million grant to establish the UC Davis Nonhuman Primate Testing Center for Evaluation of Somatic Cell Genome Editing Tools will serve the Consortium by supporting studies that advance the future treatment of human diseases with gene editing.

The new award enables researchers to test a unique delivery system that utilizes an engineered, non-infectious hepatitis E virus to orally deliver CRISPR into cells in the gastrointestinal tract of mice. They will then measure the technique’s ability to edit targeted genes. Their overarching goal is to edit APC, a gene that normally suppresses tumor growth. When when the gene is defective it can cause familial polyposis, which almost always leads to colon cancer.

“The question is how to deliver CRISPR into target cells in cancer or precancer then edit the gene,” said Lam. “You can do this relatively easily in cell culture – getting it to living cells. But to deliver CRISPR to disease tissues or organs in a living animal is a big challenge. That is our goal.”

The researchers’ multi-disciplinary approach to the effort involves three specific areas of expertise.

Lam’s combinatorial chemistry and nanodelivery work will be employed to deliver the CRISPR cargo to the targeted cells in the gut. The Cheng lab will create a non-toxic, non-infectious hepatitis E virus in the laboratory that can be used to encapsulate CRISPR for oral delivery to the mouse.

“Using protein engineering and a state-of-the art cryo-electron microscope, we have optimized the hepatitis E viral capsule as a unique and effective nanodelivery carrier,” said Cheng. “Through our structure-guided design and the evolutional advantage of a water-borne agent, our viral vector can pass through the harsh environment of the stomach and deliver the loaded gene editors to targeted cells in the gut.”

David Segal, professor in the Department of Biochemistry and Molecular Medicine and a SCGE Davis Center leader, will design the CRISPR gene-editing system.

“We are excited to be one of the groups developing new delivery technologies as part of the SCGE Consortium.” said Segal. “The unique properties of the virus will allow us to test delivery of both protein and nucleic acid forms of the editor, using state-of-the-art techniques for design and analysis. This work could lead to new treatments for diseases of the gut, including colorectal cancer.” 

For more information about the NIH genome editing awards please visit https://ncats.nih.gov/news/releases/2019/somatic-cells.

This article originally appeared on the UC Davis Health website.