Researchers from Rice University and Baylor College of Medicine are part of a national effort to accelerate genome-editing research and develop gene-editing technologies and therapies.
The goals and planned activities of the Somatic Cell Genome Editing Consortium (SCGE) were described in a paper published in Nature by more than 70 principal investigators on 45 SCGE projects funded by the National Institutes of Health.
The consortium “aims to accelerate the development of safer and more-effective methods to edit the genomes of disease-relevant somatic cells in patients, even in tissues that are difficult to reach,” according to the paper. Somatic cells include all types except sperm and egg cells, which means somatic cell mutations can affect individuals but not their offspring.
SCGE-funded groups are engaged in the development of new delivery systems for genome-editing machinery, identification of new editing enzymes, assessing the risks of genome editing and generating reporter models for detecting editing events, as well as testing in small- and large-animal models to support these efforts.
Baylor is hosting one of the consortium’s two small-animal testing centers. The effort is led by Baylor’s Jason Heaney, William Lagor and Mary Dickinson, who are developing new reporter mice to detect somatic genome editing events.
Rice’s Gang Bao, the Foyt Family Professor and chair of the Department of Bioengineering and a CPRIT Scholar in Cancer Research, is both supporting the efforts of the small-animal testing center at Baylor and leading an SCGE project that is engineering adeno-associated viruses (AAV) to deliver genome-editing enzymes to the endothelium.
“The goal of this SCGE delivery project is to engineer a modular AAV vector platform to enhance tissue-specific delivery and attach Cas9 proteins to AAV to achieve transient gene editing activity,” said Bao, an expert in CRISPR/Cas9-based genome editing and co-author of the Nature paper.
This Rice AAV delivery project is a collaborative effort that includes Xue Sherry Gao, assistant professor in chemical and biomolecular engineering at Rice; Lagor, associate professor of molecular physiology and biophysics at Baylor; Joshua Wythe, associate professor of molecular physiology and biophysics at Baylor; and Douglas Burrin, research physiologist and professor of pediatrics at Baylor and the USDA-ARS Children’s Nutrition Research Center.
Buhle Moyo in the Bao lab has been engineering the AAV capsid to attach the Cas9 protein. Michele Alves-Bezerra in the Lagor lab is developing new approaches to improve AAV delivery to endothelial cells.
“Delivery of CRISPR/Cas9 to the vasculature remains a major challenge and could have important applications to treat a wide range of diseases including atherosclerotic cardiovascular disease and macular degeneration,” Lagor said.
For Baylor’s small-animal testing center, Heaney’s lab is developing mice to detect genome-editing events like small insertion and deletion mutations, homology directed repair and off-target editing. Denise Lanza and John Seavitt are leading the mouse production efforts.
“Measuring these editing events in live animals has been a major challenge until this point,” said Heaney, associate professor of molecular and human genetics and director of the Center for Precision Medicine Models at Baylor. “The new animal models allow for identification of rare individual cells that have undergone genome editing. For example, the models now make it possible to test whether new delivery systems could enter unintended tissues, including germ cells.”
Dickinson’s lab will coordinate research activities for the grant, including developing and applying new imaging modalities to quantify genome editing with the assistance of Baylor’s Logan Hsu, assistant professor of molecular physiology and biophysics. Sophisticated imaging modalities such as light sheet microscopy and tissue clearing are being used to identify editing events with single-cell resolution within reporter mice.
Lagor’s lab serves as the genome-editing testing core, which is tasked with validation of newly generated reporter mice. This includes delivery of genome-editing enzymes such as the CRISPR/Cas9 system.
As part of the SCGE, the small-animal testing centers also provide independent validation for teams developing new delivery systems. This effort to ensure rigor and reproducibility involves independent validation of new delivery technologies in the reporter mice at Baylor. Christopher Walkey in the Lagor group is coordinating with 10 teams across the U.S. to test novel delivery systems, which include everything from engineered viruses to peptides to lipid nanoparticles. Ayrea Hurley and Alexa Martinez are testing these delivery systems in Baylor’s reporter mice.
Results from experiments in the SCGE will become part of a publicly available toolkit that will allow researchers from around the world to benefit from these cutting-edge technologies. Learn more here.
Author: MOLLY CHIU and JADE BOYD