Marco De Giorgi, So Hyun Park, Adam Castoreno, Mingming Cao, Ayrea Hurley, Lavanya Saxena, Marcel A. Chuecos, Christopher J. Walkey, Alexandria M. Doerfler, Mia N. Furgurson, M. Cecilia Ljungberg, Kalyani R. Patel, Sarah Hyde, Tyler Chickering, Stephanie Lefebvre, Kelly Wassarman, Patrick Miller, June Qin, Mark K. Schlegel, Ivan Zlatev, Jun Han, Christine Beeton, Rich Gang Li, Jong Kim, James F. Martin, Karl-Dimiter Bissig, Vasant Jadhav, Gang Bao, William R. Lagor
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Abstract
Homology-directed repair (HDR)–based genome editing is an approach that could permanently correct a broad range of genetic diseases. However, its utility is limited by inefficient and imprecise DNA repair mechanisms in terminally differentiated tissues. Here, we tested Repair Drive, a platform technology for selectively expanding HDR-corrected hepatocytes in adult mice in vivo. Repair Drive involves transient conditioning of the liver by knocking down an essential gene, fumarylacetoacetate hydrolase ( Fah ), and delivering an untargetable version of the essential gene in cis with a therapeutic transgene. We show that Repair Drive increased the percentage of correctly targeted hepatocytes in healthy wild-type mice up to 25%, which resulted in a fivefold increased expression of a therapeutic transgene, human factor IX ( FIX ). Repair Drive was well tolerated and did not induce toxicity or tumorigenesis during a 1-year follow-up. This approach may broaden the range of liver diseases that can be treated with somatic genome editing.
期刊介绍：
Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research.
The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases.
The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine.
The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
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