Illustration of DNA strands
DNA Strands

New technology delivers genome editing complexes directly to stem cells

Research supported by multi-year National Institutes of Health grant

The development of a set of strategies for delivering genome editing complexes directly to stem cells has earned a group of innovators at Case Western Reserve University School of Medicine a first-year grant of nearly $700,000 through the National Institutes of Health (NIH) Somatic Cell Genome Editing Program.

Photo of researcher John "Chip" Tilton in his lab.
John “Chip” Tilton

The work of John “Chip” Tilton, an associate professor in the Department of Nutrition, and his collaborators could revolutionize the treatment of as many as 10,000 diseases that result from single-gene mutations. The grant amount could increase up to $2.78 million if the researchers continue to hit NIH milestones.

Working in a cystic fibrosis (CF) model, Tilton’s team has developed a lentivirus-based nanoscale protein delivery (nanoPOD) platform, with a goal of using antibody-like fusion proteins to specifically target stem cells in tissues. Using this strategy, the therapy could prevent development of CF symptoms, and those of other single-gene mutation diseases for years, decades or longer.

The delivery system includes what Tilton called, “The most interesting aspect of what we’re proposing, the Trojan Horse model, which is a new way to deliver therapeutic cargoes in patients.”

In this case, the Trojan Horse consists of a patient’s cells used to manufacture nanoPODs and then reintroduced intravenously to the host. These cells are directed toward stem cells that give rise to lung and gastrointestinal tissues.

NanoPODS, purified viral capsules that have been stripped of pathogenic genetic material, then deliver CRISPR-Cas9 genome editing complexes to replace mutated cystic fibrosis transmembrane receptor genes with corrected ones, thereby preventing disease progression.

“The nanoPODs are something that is unique and innovative and specific to our lab,” said Tilton, who is also director of Immunobiology of the Center for Proteomics and Bioinformatics. He also holds secondary appointments in the Department of Molecular Biology and Microbiology and Center for RNA Science and Therapeutics.

“We’ve devised a way to modify a viral particle so that it is essentially only a shell that can still gain entry into a target cell, and deliver to the cytoplasm or nucleus of the target cell only the cargo proteins that we enclose in it,” he said.

Doing so, Tilton said, avoids one of the primary concerns of using lentivirus gene therapy: that the virus could theoretically integrate its genetic cargo into the chromosome of the cell and increase the risk of certain cancers.

Tilton’s collaborators at Case Western Reserve include Mitchell Drumm, a professor in the Department of Genetics and Genome Sciences, Chris Flask, an associate professor in the Department of Radiology, and Zhenghe “John” Wang, a professor in the Department of Genetics and Genome Sciences and the Dale H. Cowan M.D. – Ruth Goodman Blum Professor of Cancer Research.

This article was originally published Nov. 4, 2019.