What if, instead of killing cancer cells or cells about to become cancerous, you could deliver a repair package and fix them? UC Davis researchers have just been awarded $1.5 million from the National Institutes of Health (NIH) to start work towards that goal. They are working on a novel approach to deliver CRISPR genome editing machinery to gut cells to "fix" genes responsible for a rare form of familial cancer.
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 idea is to use 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 a gene called APC that normally suppresses tumor growth. 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."
Repair machine, packaging and delivery vehicle
The researchers' multi-disciplinary approach to the effort involves three specific areas of expertise.
David Segal, professor in the Department of Biochemistry and Molecular Medicine, will design the CRISPR gene-editing system -- the contents of the repair package.
Lam's combinatorial chemistry and nanodelivery work will be employed to deliver the CRISPR cargo to the targeted cells in the gut -- the packaging and address label to get the package into the cell safely.
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 -- the delivery van taking the package to its destination.
"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."
"This work could lead to new treatments for diseases of the gut, including colorectal cancer," Segal said.
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.