Developing gene therapy treatment for cardiomyopathies
Professor Eric Olson
Director, Wellstone Clinical Muscular Dystrophy Research Center
My lab studies the mechanisms of muscle gene regulation, development and disease. We have discovered many of the key gene regulatory proteins and mechanisms that guide the formation of the heart, skeletal muscle and the cardiovascular system. These discoveries have illuminated the fundamental principles of organ formation and have provided new therapeutic targets and concepts in the quest for cardiovascular therapeutics.
I am keenly interested in translation of basic science into new therapeutics. To achieve this goal, I have cofounded several biotechnology companies and have played a major role in their leadership. Finally, I have trained over 200 students and postdoctoral fellows who are emerging as the next generation of leaders in the field. I have published more than 650 papers that have been cited over 100,000 times in the literature. My h- index is 189.
I owe my success to my trainees and to my many colleagues, such as Drs. Rhonda Bassel-Duby and Ning Liu, who share my values and commitment to making impactful discoveries and translating this knowledge into new pharmacologic and genetic therapies for inherited and acquired muscle diseases in humans.
I have spent almost forty years studying the biology of muscle, which comprises 40 percent of the human body by weight. I have studied the birth, life, disease and death of muscle cells from the embryonic somite to the dystrophic limb of a muscular dystrophy patient and from the cardiac crescent to the failing human heart. My studies have spanned the full spectrum of biological life, from the muscles that empower the wings of flies to the ceaselessly beating human heart. Some of our work is summarized below.
Mechanisms of heart repair and regeneration
The inability of the adult mammalian heart to regenerate poses one of the greatest challenges to cardiovascular medicine. My laboratory demonstrated for that the hearts of newborn mice can regenerate after partial surgical resection, but this capacity is gradually lost after birth. These findings have established a powerful new model system to unlock regenerative mechanisms in the adult heart. Most recently, we showed that four cardiac transcription factors (Mef2, Hand2, Tbx5 and Gata4) can reprogram fibroblasts within the heart to a myocardial cell fate, improving cardiac function and survival following myocardial infarction. This discovery provides a new approach for heart repair, bypassing obstacles associated with cellular transplantation.
Huang, G.N., Thatcher, J.E. McAnally, J., Kong, Y., Qi, X., Tan, W., DiMaio, J.M., Amatruda, J.F., Gerard, R.D., Hill, J.A., Bassel-Duby, R., and Olson, E.N. C/EBP transcription factors mediate epicardial activation during heart development and injury. Science. 2012 338, 1599-1603. doi: 10.1126/science.1229765. PMCID:PMC3613149
Song, K., Nam, Y-J., Luo, X., Qi, X., Tan, W., Huang, G., Acharya, A., Smith, C.L., Tallquist, M.D., Neilson, E.G., Hill, J.A., Bassel-Duby, R., and Olson, E.N. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature. 2012 485, 599-604. doi: 10.1038/nature11139. PMCID:PMC3367390
Discovery of gene regulatory mechanisms of heart disease
We elucidated the mechanisms for pathological cardiac hypertrophy and heart failure and were the first to recognize the importance of the calcium-dependent phosphatase calcineurin in pathological cardiac hypertrophy and heart failure. We showed that calcium-dependent kinases also control pathological cardiac remodeling by phosphorylating histone deacetylases (HDACs), causing changes in cardiac gene expression. These findings led to the development of HDAC inhibitors as a new class of cardio-protective drugs, currently in clinical development. We also discovered diagnostic patterns of microRNAs associated with heart disease in humans and mice, and showed that these microRNAs regulate many aspects of cardiovascular biology, including myocyte growth and survival, contractility, energy metabolism, fibrosis, and angiogenesis. We discovered that myosin heavy chain genes encode microRNAs in their introns and that these microRNAs control cardiac contractility, metabolism and stress responsiveness. Recently, we discovered that several long non-coding RNAs actually encode small unannotated micropeptides that control muscle function.
Molkentin, J.D., Lu, J., Antos, C.L., Markham, B., Richardson, J., Robbins, J., Grant, S. and Olson, E.N. 1998. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93, 215-228. doi: 10.1016/s0092-8674(00)81573-1. PMID:9568714
Zhang, C.L., McKinsey, T.A., Chang, S., Antos, C.A., Hill, J.A., and Olson, E.N. 2002. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 110, 479-488. doi: 10.1016/s0092-8674(02)00861-9. PMID:12202037
Nelson, B.R., Makarewich, C.A., Anderson, D.M., Winders, B.R., Troupes, C.D., Wu, F., Reese, A.L., McAnally, J.R., Chen, X., Kavalali, E.T., Cannon, S.C., Houser, S.R., Bassel-Duby, R., and Olson, E.N. 2016. A peptide encoded by a transcript annotated as long noncoding RNA enhances SERCA activity in muscle. Science, 351, 271-275. doi: 10.1126/science.aad4076. PMCID: PMC4892890
Molecular pathways for skeletal muscle development and disease
My trainees discovered many of the genes and regulatory pathways that control skeletal muscle development and disease. We discovered myogenin, an essential regulator of skeletal muscle development, and MEF2, which controls the differentiation of all muscle cell types. The formation of skeletal muscle fibers requires fusion of myoblasts. Recently, we discovered the unique muscle-specific membrane protein, called Myomaker, which is sufficient and necessary for fusion of myoblasts. We have also advanced genomic editing strategies for the correction of muscular dystrophy
Millay, D.P., O'Rourke, J.R., Sutherland, L.B., Bezprozvannaya, S., Shelton, J.M., Bassel-Duby, R.,and Olson, E.N. 2013. Myomaker is a membrane activator of myoblast fusion and muscle formation. Nature 499, 301-305. doi: 10.1038/nature12343. PMCID:PMC3739301
Genetic correction of DMD
We have pioneered an approach to correct genetic mutations responsible for DMD and have optimized and tested this approach in mice, dogs and human cells.
Long, C., McAnally, J.R., Shelton, J.M., Mireault, A. A., Bassel-Duby, R. and Olson, E.N. 2014. Prevention of muscular dystrophy in mice by CRISPR/Cas9-mediated editing of germline DNA. Science 345, 1184-1188. doi: 10.1126/science.1254445. PMCID:PMC4398027
Long, C., Amoasii, L., Mireault, A.A., McAnally, J.R., Li, H., Sanchez-Ortiz, E., Bhattacharyya, S., Shelton, J.M., Bassel-Duby, R., and Olson, E.N. 2016. Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science, 351, 400-403. doi: 10.1126/science.aad5725. PMCID: PMC476062
Amoasii, L., Hildyard, J.C.W., Li, H., Sanchez-Ortiz, E., Mireault, A., Caballero, D., Harron, R., Stathopoulou, T-R., Massey, C., Shelton, J.M., Bassel-Duby, R., Piercy, R.J., and Olson, E.N. 2018. Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy. Science, 362, 86-91. doi: 10.1126/science.aau1549. PMCID: PMC6205228
Delineation of gene regulatory networks of muscle formation
My laboratory discovered key regulatory genes that govern the formation of the heart in organisms ranging from fruit flies to mammals and demonstrated how these genes function with a network to control cell fate determination, differentiation and morphogenesis within the developing heart. We showed that MEF2 was required for heart formation and we discovered myocardin and myocardin-related transcription factors, which govern cardiovascular cell fates and development of the heart and blood vessels. We also discovered the first chamber-restricted transcription factors, Hand1 and Hand2, which are expressed in the left and right ventricles, respectively, of the heart. We demonstrated that these factors control growth of the specific cardiac chamber in which they are expressed, providing the first evidence that a single gene defect could disrupt a specific region of the heart. These and other gene regulatory proteins discovered in our lab provided an initial genetic blueprint for understanding normal and abnormal heart development.
Srivastava, D., Cserjesi, P. and Olson, E.N. 1995. New subclass of bHLH proteins required for cardiac morphogenesis. Science, 270, 1995-1999. doi: 10.1126/science.270.5244.1995. PMID:8533092