Associate Professor; Director
Genetic and Epigenetic Origins of
Disease Program, Cardiovascular
Institute, Perelman School of Medicine
Location: Smilow TRC 11-104
Admin: Kyndall Hawkins
My research laboratory focuses on:
(1) the discovery of novel genetic variants associated with disease and its risk factors; (2) understanding how these genetic variants influence gene function; (3) characterizing the implicated genes and their effects on disease phenotypes; and (4) using these insights to initiate the development of novel therapeutics. A key element of my research program is to use human model systems and humanized model systems—e.g., genetically modified human embryonic stem cells and induced pluripotent stem cells and tissue types differentiated from these cells, mice in which organs such as the liver or portions of the mouse genome have been replaced with the human equivalents—to study human genetic variation. Our work in discovering and characterizing SORT1 and ANGTPL3 as low-density-lipoprotein cholesterol genes using genome-wide association studies and exome sequencing studies and subsequent functional analyses in mice and cell-based models (Musunuru et al., Nature 2010; Musunuru et al., N Engl J Med 2010; Stitziel et al., J Am Coll Cardiol 2017) has provided a template for the investigation of many genetic loci found to be associated with blood lipid levels (Teslovich et al., Nature 2010; Pashos et al., Cell Stem Cell 2017; Liu et al., Nat Genet 2017) and other cardiometabolic phenotypes. We have established protocols by which to use engineered TAL effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated 9 (Cas9) to introduce genetic alterations (knockouts, knockins, reporters) into human cells for disease modeling and drug screening (Ding et al., Cell Stem Cell 2013a; Ding et al., Cell Stem Cell 2013b; Veres et al., Cell Stem Cell 2014; Pashos et al., Cell Stem Cell 2017). We are also working to develop therapeutic applications of genome editing to prevent cardiovascular diseases (Ding et al., Circ Res 2014; Wang et al., Arterioscler Thromb Vasc Biol 2016; Chadwick et al., Arterioscler Thromb Vasc Biol 2017; Chadwick et al., Circulation 2018).
Lay Version Explanation:
Developing a “vaccination” against heart attack.
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). The treatment has been shown to work extremely well in mice, and now he is working to make the treatment as effective and safe as possible before testing it in people who are at extremely high risk for suffering a heart attack. If it works well, it could be offered to the general population as a “vaccination”.
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.
Chadwick AC, Evitt NH, Lv W, Musunuru K. Reduced blood lipid levels with in vivo CRISPR-Cas9 base editing of ANGPTL3. Circulation. In the press.
Wang X, Raghavan A, Peters DT, Pashos EE, Rader DJ, Musunuru K. Interrogation of the atherosclerosis-associated SORT1 (sortilin 1) locus with primary human hepatocytes, induced pluripotent stem cell-hepatocytes, and locus-humanized mice. Arterioscler Thromb Vasc Biol. 2018;38:76-82.
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.
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.
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.
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.
Wang X, Raghavan A, Chen T, Qiao L, Zhang Y, Ding Q, Musunuru K. CRISPR-Cas9 targeting of PCSK9 in human hepatocytes in vivo. Arterioscler Thromb Vasc Biol. 2016;36:783-786.
Ding Q, Strong A, Patel KM, Ng SL, Gosis BS, Regan SN, Cowan CA, Rader DJ, Musunuru K. Permanent alteration of PCSK9 with in vivo CRISPR-Cas9 genome editing. Circ Res. 2014;115:488-492.
Veres A, Gosis BS, Ding Q, Collins R, Ragavendran A, Brand H, Erdin S, Cowan CA, Talkowski ME, Musunuru K. Low incidence of off-target mutations in individual CRISPR-Cas9 and TALEN targeted human stem cell clones detected by whole-genome sequencing. Cell Stem Cell. 2014;15:27-30.
Ding Q, Regan SN, Xia Y, Oostrom LA, Cowan CA, Musunuru K. Enhanced efficiency of human pluripotent stem cell genome editing through replacing TALENs with CRISPRs. Cell Stem Cell. 2013;12:393-394.
Ding Q, Lee YK, Schaefer EA, …, Chung RT, Musunuru K, Cowan CA. A TALEN genome-editing system for generating human stem cell-based disease models. Cell Stem Cell. 2013;12:238-251.
Musunuru K, Pirruccello JP, Do R, et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med. 2010;363:2220-2227.
Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, et al. Biological, clinical, and population relevance of 95 loci for blood lipids. Nature. 2010;466:707-713.
Musunuru K, Strong A, Frank-Kamenetsky M, et al. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature. 2010;466:714-719.