Method by which to restart the proliferation of heart muscle cells after production cease with development.
At some point in human development, the number of cardiomyocytes—the heart muscle cells responsible for generating contractile forces—is firmly established at a set amount. This amount is referred to as an individual’s “endowment,” and after the endowment is established, these cardiomyocytes must last a lifetime. A reduced endowment induces heart failure or acute myocardial infarction associated with a high mortality rate; in particular, infants with congenital heart disease (CHD) have decreased cardiomyocyte proliferation early on, resulting in a 20% lower endowment that leads to significant lifetime morbidity and mortality. CHD occurs in about 1% of live births in the US, and even after successful surgical repair, patients with CHD are at a significantly increased risk for heart failure and arrhythmia. Medications to alter cardiomyocyrte proliferation do not exist, and regenerative strategies to increase or prolong proliferation are highly sought after as a solution to infant CHD, myocardial functions, and other heart diseases.
Technology Description
Researchers have identified a new molecular connection between the cellular mechanisms of endowment regulation and a unique molecular pathway implicated in CHD that can be targeted to design new therapeutics. In CHD, mononucleated cardiomyocytes are converted to binucleated cardiomyocytes, which cannot divide, prematurely stopping proliferation. Administration of β-blockers, which are commonly prescribed to manage chronic heart failure and high blood pressure, suppresses the molecular pathway responsible for formation of binucleated cardiomyocytes, thereby promoting myocardial regeneration and increasing the overall endowment. Delivery of β-blockers within a novel therapeutic window—specifically within six months of birth—can treat congenital heart disease in pediatric populations and restore endowment to healthy levels. The use of β-blockers in infants as well as the identified period of maximum impact, along with an assay to monitor the outcome, represent a new paradigm in the treatment of a devastating pediatric disease.Advantages
Treatment is widely accessible and affordable, as β-blockers are FDA-approved, safe, and already widely commercialized
Reduces the need for invasive and dangerous surgery
Significantly increases life expectancy as well as quality of lifeApplications
Strengthening the hearts of infants afflicted with CHD by increasing cardiomyocyte endowment
Inducing cardiomyocyte proliferation in a patient after a myocardial infarction
Prevention of ventricular remodeling, heart failure, and arrhythmia development in pediatric patients
Assessment of ideal period for administration of β-blockers; i.e., within the first six months after birth
Monitoring and quantifying the effects of treatment by determining cell proliferation or regenerationStage of Development
In vivo dataIP Status
Provisional patent application filed
InnovatorsBernard Kuhn, MD
Associate Director, Richard King Mellon Foundation for Pediatric Research
Associate Professor, Department of Pediatrics, University of Pittsburgh School of Medicine
Director, Research in Cardiology, UPMC Children’s Hospital of Pittsburgh
Director, Pediatric Institute for Heart Regeneration and Therapeutics
Dr. Kuhn’s research interests include understanding the unique workings of heart muscle cells and pioneering new techniques to make cardiomyocytes replicate and proliferate to enable self-healing of the heart. He is the recipient of numerous grants and awards, including the American College of Cardiology’s Young Investigator Award, the Basil O’Connor Award from the March of Dimes Birth Defects Foundation, and the Scientist Development Grant from the American Heart Association.Education
PhD, Freie Universitat, Berlin, Germany
MD, Freie Universitat, Berlin, GermanySelected Publications
Liu H, Zhang CH, … Kühn B, et al. Control of cytokinesis by β-adrenergic receptors indicates an approach for regulating cardiomyocyte endowment. Sci Transl Med. 2019 Oct 9;11(513). pii: eaaw6419. doi: 10.1126/scitranslmed.aaw6419. PubMed PMID: 31597755.
Lal S, Kühn B. Regenerating Hearts by Arresting Development With Hypothyroidism. Circ Res. 2019 Jun 7;124(12):1725-1726. doi: 10.1161/CIRCRESAHA.119.315106. Epub 2019 Jun 6. PubMed PMID: 31170042; PubMed Central PMCID: PMC6557294.
Missinato MA, Saydmohammed M, Zuppo DA, Rao KS, Opie GW, Kühn B, Tsang M. Dusp6 attenuates Ras/MAPK signaling to limit zebrafish heart regeneration. Development. 2018 Mar 6;145(5). pii: dev157206. doi: 10.1242/dev.157206. PubMed PMID: 29444893; PubMed Central PMCID: PMC5868992.
Gong Z, Tasset I, Diaz A, Anguiano J, Tas E, Cui L, Kuliawat R, Liu H, Kühn B, Cuervo AM, Muzumdar R. Humanin is an endogenous activator of chaperone-mediated autophagy. J Cell Biol. 2018 Feb 5;217(2):635-647. doi: 10.1083/jcb.201606095. Epub 2017 Nov 29. PubMed PMID: 29187525; PubMed Central PMCID: PMC5800795.