UCSB Professor Collaborates on New Gene Repair Technique That Promises Advances in Regenerative Medicine

Using human pluripotent stem cells and DNA-cutting protein from meningitis bacteria, researchers from UC Santa Barbara, the Morgridge Institute for Research at the University of WisconsinMadison, and Northwestern University have created an efficient way to target and repair defectivegenes.

Published today in the Proceedings of the National Academy of Sciences, the teams findings demonstrate that the novel technique is much simpler than previous methods and establishes the groundwork for major advances in regenerative medicine, drug screening, and biomedicalresearch.

Principal investigator James A. Thomson, co-director of biology at UCSBs Center for Stem Cell Biology and Engineering and professor in the campuss Department of Molecular, Cellular and Developmental Biology, said the discovery holds many practical applications, including paving a new route for correcting genetic disorders. Thomson is also director of regenerative biology at the Morgridge Institute, serves as the James Kress Professor of Embryonic Stem Cell Biology at the University of WisconsinMadison, and is a John D. MacArthur professor at UWMadisons School of Medicine and PublicHealth.

According to the papers lead author, Zhonggang Hou of the Morgridge Institutes regenerative biology team, the technique has the potential to repair any genetic defect, including those responsible for some forms of breast cancer, Parkinsons, and other diseases. The fact that it can be applied to human pluripotent stem cells opens the door for meaningful therapeutic applications, saidHou.

The research team focused on Neisseria meningitidis bacteria because it is a good source of the Cas9 protein needed for precisely cleaving damaged sections of DNA. Using different types of small RNA molecules, the research team was able to guide this protein, engendering the careful removal, replacement, or correction of problem genes. This represents a step forward from other recent technologies built upon proteins, such as zinc finger nucleases and transcription activator-like effector nucleases, said Yan Zhang of Northwestern University, second author of thepaper.

These previous gene correction methods required engineered proteins to help with the cutting. The researchers said scientists can synthesize RNA for the new process in as little as one to three days, compared with the weeks or months needed to engineer suitableproteins.

Human pluripotent stem cells can proliferate indefinitely and they give rise to virtually all human cell types, making them invaluable for regenerative medicine, drug screening, and biomedical research, Thomson said. This collaboration has taken us further toward realizing the full potential of these cells because we can now manipulate their genomes in a precise, efficientmanner.

Erik Sontheimer, another principal investigator and the Soretta and Henry Shapiro Research Professor of Molecular Biology in Northwesterns department of molecular biosciences, Center for Genetic Medicine, and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, said the teams results also offer hopeful signs about the safety of thetechnique.

A major concern with previous methods involved inadvertent or off-target cleaving, raising issues about the potential impact in regenerative medicine applications, said Sontheimer. Beyond overcoming the safety obstacles, the systems ease of use will make what was once considered a difficult project into a routine laboratory technique, catalyzing futureresearch.

Also contributing to the study, which was supported by funding from the National Institutes of Health, the Wynn Foundation, and the Morgridge Institute for Research, were Nicholas Propson, Sara Howden, and Li-Fang Chu from the Morgridge Institute forResearch.

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UCSB Professor Collaborates on New Gene Repair Technique That Promises Advances in Regenerative Medicine