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Kiran Musunuru, M.D., Ph.D., M.P.H., M.L., M.R.A.Kiran Musunuru

Barry J. Gertz Professor for Translational Research

Co-Director, Penn Medicine/CHOP Orphan Disease Center
Director, Genetic and Epigenetic Origins of Disease Program
Cardiovascular Institute
Scientific Director, Center for Inherited Cardiovascular Disease
Perelman School of Medicine

Biography:

An actively practicing cardiologist and committed teacher, Kiran Musunuru, M.D., Ph.D., M.P.H., M.L., M.R.A., is the Barry J. Gertz Professor for Translational Medicine in the Perelman School of Medicine at the University of Pennsylvania. His research focuses on the development of novel gene editing therapies for the treatment of cardiovascular and metabolic diseases. He is a recipient of the Presidential Early Career Award for Scientists and Engineers from the White House, the Pennsylvania Governor's Keystone Award, the American Heart Association's Award of Meritorious Achievement and Joseph A. Vita Award, the American Philosophical Society's Judson Daland Prize for Outstanding Achievement in Clinical Investigation, the American Federation for Medical Research's Outstanding Investigator Award, Harvard University's Fannie Cox Prize for Excellence in Science Teaching, and the University of Pennsylvania's Jane M. Glick Graduate Student Teaching Award. He recently served as Editor-in-Chief of the scientific journal Circulation: Genomic and Precision Medicine and is the current Editor-in-Chief of The American Journal of Human Genetics. He is author of The CRISPR Generation: The Story of the World's First Gene-Edited Babies and Genome Editing: A Practical Guide to Research and Clinical Applications.

 

Lay Version Explanation of Research:

 

Scientific Explanation of Research:

 

Past research projects have included:

Developing treatments to protect against heart attack and other chronic diseases.

Cardiovascular disease is the leading cause of death worldwide, not just in the U.S. but even in the poorest countries in the world. It has already become the next big global health threat. Dr. Musunuru is using a new technology called “gene editing” to modify genes in the liver so as to permanently reduce a person’s cholesterol levels and protect against heart attack and stroke—with a single shot whose effects would last for the lifetime (instead of having to take pills every day). He has shown the treatment to work extremely well in mice and monkeys, and it is now being tested in clinical trials in people who are at extremely high risk for suffering a heart attack. If it works well, it could eventually be offered to the general population as a voluntary “vaccination” against heart disease. Dr. Musunuru is now applying the same technology to other diseases.

 

Discovering new heart attack genes.

Dr. Musunuru has been studying people with naturally born low cholesterol levels in order to figure out whether there are genetic causes. He discovered that there are people with rare “good” mutations in a gene called ANGPTL3 that not only reduce both cholesterol and fat levels in the blood but also substantially protect against heart attack and, to a lesser degree, against type 2 diabetes. At the same time, these people who have won the “genetic lottery”, so to speak, do not suffer any bad effects from the “good” mutations. This work recommends ANGPTL3 as a target against which to develop new therapies, which is in progress.

 

Determining what your genes mean for your heart health.

More and more people are having their genes sequenced, and it turns out that everybody has dozens of mutations that are unique to them. Fortunately, most of the mutations are benign and do not affect one’s health, but it is possible that one or more of the mutations increases the risk of a serious disease. Dr. Musunuru would like to be able to determine whether a person’s mutations signify risk of heart disease before the person develops the disease, so as to give preventive therapy early. He is using adult stem cells into which he inserts patient mutations, turns them into heart muscle cells in a dish, and then studies the properties of the muscle cells to determine whether there are signs of disease caused by the mutations. This is letting him sort out whether a particular mutation is benign or makes a person vulnerable to heart disease, long before the disease occurs.

 

Selected Publications

  1. Davis JR, Wang X, Witte IP, …, Seidah NG, Musunuru K, Liu DR. Efficient in vivo base editing via single adeno-associated viruses with size-optimized genomes encoding compact adenine base editors. Nat Biomed Eng. 2022; online ahead of print.
  2. Banskota S, Raguram A, Suh S, …, Musunuru K, Palczewski K, Liu DR. Engineered virus-like particles for efficient in vivo delivery of therapeutic proteins. Cell. 2022;185:250-265.e16.
  3. Musunuru K, Chadwick AC, Mizoguchi T, et al. In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates. Nature. 2021;593:429-434.
  4. Sandrone S, Scott G, Anderson WJ, Musunuru K. Active learning-based STEM education for in-person and online learning. Cell. 2021;184:1409-1414.
  5. Shah PP, Lv W, Rhoades JH, …, Prosser BL, Musunuru K, Jain R. Pathogenic LMNA variants disrupt cardiac lamina-chromatin interactions and de-repress alternative fate genes. Cell Stem Cell. 2021;28:938-954.e9.
  6. Morley MP, Wang X, Hu R, …, Margulies KB, Musunuru K, Cappola TP. Cardioprotective effects of MTSS1 enhancer variants. Circulation. 2019;139:2073-2076.
  7. Rossidis AC, Stratigis JD, Chadwick AC, …, Morrisey EE, Musunuru K, Peranteau WH. In utero CRISPR-mediated therapeutic editing of metabolic genes. Nat Med. 2018;24:1513-1518.
  8. Lv W, Qiao L, Petrenko, Li W, Owens AT, McDermott-Roe C, Musunuru K. Functional annotation of TNNT2 variants of uncertain significance with genome-edited cardiomyocytes. Circulation. 2018;138:2852-2854.
  9. Chadwick AC, Evitt NH, Lv W, Musunuru K. Reduced blood lipid levels with in vivo CRISPR-Cas9 base editing of ANGPTL3. Circulation. 2018;137:975-977.
  10. Liu DJ, Peloso GM, Yu H, …, Musunuru K, Willer CJ, Kathiresan S. Exome-wide association study of plasma lipids in >300,000 individuals. Nat Genet. 2017;49:1758-1766.
  11. Chadwick AC, Wang X, Musunuru K. In vivo base editing of PCSK9 (proprotein convertase subtilisin/kexin type 9) as a therapeutic alternative to genome editing. Arterioscler Thromb Vasc Biol. 2017;37:1741-1747.
  12. Stitziel NO, Khera AV, Wang X, …, Saleheen D, Musunuru K, Kathiresan S. ANGPTL3 deficiency and protection against coronary artery disease. J Am Coll Cardiol. 2017;69:2054-2063.
  13. Pashos EE, Park Y, Wang X, …, Rader DJ, Brown CD, Musunuru K. Large, diverse population cohorts of hiPSCs and derived hepatocyte-like cells reveal functional genetic variation at blood lipid-associated loci. Cell Stem Cell. 2017;20:558-570.