Base Editing and Prime Editing: Engineered Proteins that Precisely Correct Pathogenic Mutations in Cells, Animals, and Patients

Event Details

Type

Friday Lecture Series

Speaker(s)

David R. Liu, Ph.D., Richard Merkin Professor, director of the Merkin Institute of Transformative Technologies in Healthcare, Thomas Dudley Cabot Professor of the Natural Sciences, department of chemistry and chemical biology, Harvard University; member and vice-chair of the faculty, The Broad Institute of MIT and Harvard; investigator, Howard Hughes Medical Institute

Speaker bio(s)

Dr. Liu will describe the development and therapeutic application of two precision gene editing technologies that install or correct targeted mutations without requiring double-strand DNA breaks, thereby minimizing undesired consequences of chromosomal cleavage. His team developed base editors, proteins that directly perform chemistry on individual DNA bases in living cells to install or correct mutations at targeted positions in genomic DNA. They recently engineered CRISPR-free, all-protein base editors that enabled the first purposeful changes in the sequence of mitochondrial DNA in living cells. By integrating base editors with ex vivo and in vivo delivery strategies that deliver therapeutic proteins, they rescued animal models of human genetic diseases including sickle-cell disease, progeria, and spinal muscular atrophy (SMA). Single-AAV base editing systems enhance the safety and practicality of in vivo base editing. Their development of engineered virus-like particles (eVLPs) provide additional in vivo delivery methods for gene editing proteins that minimize off-target editing and the risk of oncogenic DNA integration. Base editors are in at least six clinical trials to treat diseases including familial hypercholesterolemia, sickle-cell disease, beta-thalassemia, and T-cell leukemia. The first clinical outcomes from ex vivo base editing and from in vivo base editing have also been reported, demonstrating benefit to T-cell leukemia patients and to hypercholesterolemia patients, respectively. Dr. Liu will also describe prime editors, engineered proteins that directly write new genetic information into a specified DNA site, replacing the original sequence, without requiring double-strand DNA breaks or donor DNA templates. Prime editing can mediate any base substitutions, deletions, and/or insertions of up to ~200 base pairs in living cells in vitro and in vivo, and has been applied to directly install or correct pathogenic alleles that previously could not be corrected in therapeutically relevant cells. They illuminated the cellular determinants of prime editing outcomes, and used the resulting insights to develop new prime editing systems with substantially higher editing efficiencies and product purities. Most recently, they used phage-assisted continuous evolution (PACE) to evolve a suite of sixth-generation prime editors (PE6a-6g), which each evolved to specialize in different types of prime edits. The combination of prime editing and site-specific recombinases enable programmable gene-sized (>5 kb) integration and inversion at loci of our choosing in human cells. Prime editing has recently been used to rescue animal models of genetic diseases including sickle-cell disease, metabolic liver diseases, and genetic blindness, and is anticipated to be cleared for clinical trials in 2024. Base editing and prime editing enable precise target gene correction, in addition to target gene disruption, in a wide range of organisms with broad implications for the life sciences and therapeutics.

David R. Liu’s research integrates chemistry and evolution to illuminate biology and enable next-generation therapeutics. His major research interests include the engineering, evolution, and in vivo delivery of genome editing proteins such as base editors and prime editors to study and treat genetic diseases; the evolution of proteins with novel therapeutic potential using phage-assisted continuous evolution (PACE); and the discovery of bioactive synthetic small molecules and synthetic polymers using DNA-templated organic synthesis and DNA-encoded libraries. Base editing—the first general method to perform precision gene editing without double-stranded breaks, and a Science 2017 Breakthrough of the Year finalist—as well as prime editing, PACE, and DNA-templated synthesis are four examples of technologies pioneered in his laboratory. These technologies are used by thousands of labs around the world and have enabled the study and potential treatment of many genetic diseases. Four base editing clinical trials are already underway to treat leukemia, hypercholesterolemia, sickle-cell disease, and beta-thalassemia, and the first clinical benefit of a base edited therapeutic in a T-cell leukemia trial has been reported.

Liu graduated first in his class at Harvard College in 1994. During his doctoral research at UC Berkeley, Liu initiated the first general effort to expand the genetic code in living cells. He earned his Ph.D. in 1999 and became assistant professor of chemistry and chemical biology at Harvard University in the same year. He was promoted to associate professor in 2003 and to full professor in 2005. Liu became a Howard Hughes Medical Institute investigator in 2005 and joined the JASONs, academic science advisors to the U.S. government, in 2009. In 2016 he became a Core Institute Member and Vice-Chair of the Faculty at the Broad Institute of MIT and Harvard, and Director of the Chemical Biology and Therapeutics Science Program.

Liu has published more than 240 papers and is the inventor on more than 90 issued U.S. patents. Liu has been elected to the U.S. National Academy of Sciences, the U.S. National Academy of Medicine, and the American Association for the Advancement of Science. He is the 2022 King Faisal Prize Laureate in Medicine. He has earned several University-wide distinctions for teaching at Harvard, including the Joseph R. Levenson Memorial Teaching Prize, the Roslyn Abramson Award, and a Harvard College Professorship. His research accomplishments have earned distinctions including the Ronald Breslow Award for Biomimetic Chemistry, the American Chemical Society David Perlman Award, ACS Chemical Biology Award, the American Chemical Society Pure Chemistry Award, the Arthur Cope Young Scholar Award, the NIH Marshall Nirenberg Lecturer, and awards from the Sloan Foundation, Beckman Foundation, NSF CAREER Program, and Searle Scholars Program. In 2016, 2019, and 2020 he was named one of the Top 20 Translational Researchers in the world by Nature Biotechnology, and was named one of Nature’s 10 researchers in world and to the Foreign Policy Leading Global Thinkers in 2017. Liu is the founder or co-founder of several public and private biotechnology and therapeutics companies, including Beam Therapeutics, Prime Medicine, Editas Medicine, Pairwise Plants, Exo Therapeutics, Chroma Medicine, Resonance Medicine, and Nvelop Therapeutics.

FLS lectures will take place in Caspary Auditorium and virtually via Zoom. We recommend virtual participants log out of VPN prior to logging in to Zoom. Please do not share the link or post on social media. This talk will be recorded for the RU community.

Open to

Tri-Institutional