Ethan M. Goldberg, MD, PhD- The Children’s Hospital of Philadelphia
David R. Liu, PhD- MIT and Harvard University
Base editing for the treatment and prevention of Dravet syndrome
Research Grant- $250,000, 2 years
Summary from the Investigators: Dravet syndrome is caused by genetic mutations in the gene SCN1A that encodes the voltage-gated sodium channel subunit known as Nav1.1, which is important for the electrical activity of seizure-suppressing neurons in the brain known as parvalbumin-expressing fast-spiking interneurons. Approximately 40% of the causative mutations are single base pair mutations that lead to a complete loss of Nav1.1 protein. Correction of this single base pair mutation could represent an entirely new treatment or preventative therapy. Base editing offers the promise of such a solution, a technique that uses the Nobel Prize-winning method of CRISPR/Cas9 gene editing to correct single base pair mutations without off-target (so-called “bystander”) effects that so far have previously raised concerns with the application of CRISPR/Cas9 technology to the treatment of human disease. Base editing has already shown efficacy for treatment/prevention of a range of diseases in preclinical mouse models. Here, a highly innovative world leader in the development of base editing (Dr. David Liu at Harvard University/Broad Institute) and a domain expert in Dravet syndrome (Dr. Ethan Goldberg at The Children’s Hospital of Philadelphia) team up to attempt to develop and apply a base editing strategy for Dravet syndrome in a validated mouse model. The applicants will refine a base editing approach for Dravet syndrome and then test its ability to prevent febrile seizures, epilepsy, and mortality in experimental mice, and to reverse the abnormalities seen in parvalbumin-expressing interneurons. This work would provide important data to support the further development of such an approach for potential future application in human patients, which could be truly transformative for patients and their families struggling with what is an incurable and largely untreatable disorder that affects 1 in 14,000 children born in the U.S. and around the World.
About the Investigators:
Ethan Goldberg is Associate Professor in the Division of Neurology at The Children’s Hospital of Philadelphia and Departments of Neurology and Neuroscience at The University of Pennsylvania Perelman School of Medicine. He is an Attending Physician and Director of the Epilepsy NeuroGenetics Initiative (ENGIN) at CHOP where he specializes in the diagnosis and care of children with complex
neurological disorders including epilepsy, developmental delay/intellectual disability, and autism spectrum disorder. His biomedical research lab studies basic mechanisms of childhood epilepsy and other neurodevelopmental disorders, with a particular interest in ion channelopathies and how genetic variation in ion channel genes leads to human disease. His lab uses a range of approaches including:
human and mouse genetics; ion channel, cellular and synaptic neurophysiology; pharmacology; induced pluripotent stem cell technology and cell-based therapy; behavior; and imaging approaches including two-photon microscopy in experimental systems.
David R. Liu is the Richard Merkin Professor and director of the Merkin Institute of Transformative Technologies in Healthcare, vice-chair of the faculty at the Broad Institute of MIT and Harvard, the Thomas Dudley Cabot Professor of the Natural Sciences at Harvard University, and a Howard Hughes Medical Institute (HHMI) investigator. 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 treatment of genetic diseases. At least 11 clinical trials using base editing or prime editing are already underway to treat diseases including leukemias, hypercholesterolemia, sickle-cell disease, and beta-thalassemia, and chronic granulomatous disease. The first clinical benefits of both ex vivo and in vivo base editing—including young T-cell leukemia patients whose lives were saved by base editing—have already 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 PhD 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 270 papers and is the inventor on more than 110 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, and the 2024 Jacob and Louise Gabbay Award recipient. 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 ASGCT Outstanding Achievement Award, the Ian Scott Medal for Excellence in Biological Chemistry Research, 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, 2020, and 2021 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. Liu was named as a leading global thinker by the Foreign Policy Leading Global Thinkers in 2017, to the STATUS List of 46 leaders in health, medicine, and science by STAT News, and as one of the “Most Influential People in Biopharma in 2023” by Fierce Biotech. 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, Chroma Medicine, Exo Therapeutics, and Nvelop Therapeutics.
Outside of the lab, Liu pursues a variety of hobbies at the intersection of science and art, including photography around the world, raising large bonsai trees indoors under LED light canopies he designed, creating art from wood, metal, stone, and/or electronic components, and painting.
