By creating a unique nanocapsule capable of delivering the CRISPR gene editing tool safely to the brain, a team of researchers led by University of Wisconsin-Madison Vilas Distinguished Professor of biomedical engineering and Wisconsin Institute for Discovery faculty member Shaoqin “Sarah” Gong hopes to enable precision treatments for neurodegenerative diseases.
The group will use a new grant of $2.3 million from the National Institutes of Health (NIH) to continue to push its novel nonviral delivery system forward after proving its gene editing effectiveness and efficiency during the UG3 phase of the project in a two-stage (UG3/UH3) funding mechanism.
The project, part of NIH’s Somatic Cell Genome Editing Program, is a collaboration among Gong and UW-Madison colleagues Krishanu Saha (associate professor of biomedical engineering and cell and gene therapy impact leader at the Grainger Institute), Marina Emborg (professor of medical physics and senior scientist with the Wisconsin National Primate Research Center (WNPRC)) and Jon Levine (professor of neuroscience and WNPRC director), as well as former UW-Madison faculty member Subhojit Roy, who’s now at the University of California San Diego.
While viral vectors are the standard delivery method for gene editing, they raise safety concerns and fall short in targeting specificity. Existing nonviral alternatives haven’t proven viable, either, for a host of technical reasons.
Gong and her collaborators have developed a small, versatile nanocapsule that can safely and efficiently deliver the genome editors to different cell types. While the researchers are currently focusing on neurons—specifically the amyloid precursor protein (APP) gene, a gene relevant to Alzheimer’s disease—they previously employed it to make edits in the eye and skeletal muscle cells of mice, publishing their results in the journal Nature Nanotechnology.
Gong, Saha and several of their lab members also worked with the Wisconsin Alumni Research Foundation to secure a U.S. patent for the nanocapsule delivery system in May 2021. Saha’s lab designed the RNA-guided CRISPR-Cas9 gene editing tool and has also led the genomic and transcriptomic analysis portions of the project.
“This nanoparticle is very stable in the extracellular space, but it breaks down inside the cell and releases the payload,” says Gong, whose lab specializes in creating nanocarriers for various targeted medical therapies. “And it can be conjugated with all sorts of targeting ligands, so it can be used with other types of cells, too, not just neurons. Thus, it can be potentially used to treat many different kinds of genetic diseases.”
During the next phase (UH3) of the project, Gong’s lab will work on further optimizing the nanocapsules and scaling up production ahead of testing in nonhuman primates. Emborg and Roy’s labs will analyze the APP editing and biosafety in primate brains using several different techniques. Saha’s lab will be in charge of genomic analysis. Levine will contribute to experimental plan and data analysis. If the system continues to prove successful, it could lead to a clinical trial.