Central Nervous System is the processing centre of the body and consists of the brain and the spinal cord. Both of these are protected by three layers of membranes known as meninges.
Liver is the largest internal organ in the body. It is essential for digestion of food and elimination of toxic substances from the body. Liver problems can be caused by a variety of genetic and non genetic factors such as viruses, alcohol use and obesity. Damage of the liver can lead to liver failure, and a build up of toxin in the blood leading to life threatening conditions.
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system that are mostly attached by tendons to bones of the skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscle tissue, and are often known as muscle fibers. The muscle tissue of a skeletal muscle is striated – having a striped appearance due to the arrangement of the sarcomeres.
In 2017, Novoheart filed a patent application with the United States Patent and Trademark Office (USPTO) for a versatile bioreactor platform for culturing, stimulating, and monitoring the function of multiple engineered human-tissue organoids. The proprietary bioreactor system, combines hardware for organoid maintenance, intervention, and monitoring, together with customized software for seamless data processing and analysis. The system, is designed to increase throughput, deliver strengthened consistency, and extend stimulation and monitoring capabilities. The modular design of the bioreactor allows multiple organoids to be combined for increased throughput of the semi-automated culture and testing process. Ultimately, the new technology enhances Novoheart’s capacity and further expands its ability to identify promising bioactive therapeutics, classify toxicity of unknown drugs and pioneer innovative methods of addressing diseases or disorders.
This technology applies to other mini-organs such as mini-Liver, -Lungs, -Gut, -Vasculature, etc, with circulation powered by the mini-Heart, that forms the basis of our mini-Life Platform. (Learn more details for the mini-Life Platform)
Keung W, Chan PKW, Backeris PC, Lee EK, Wong N, Wong AOT, Wong GKY, Chan CWY, Fermini B, Costa KD, Li RA. Human Cardiac Ventricular-Like Organoid Chambers and Tissue Strips From Pluripotent Stem Cells as a Two-Tiered Assay for Inotropic Responses. Clin Pharmacol Ther. 2019 Aug;106(2):402-414. doi: 10.1002/cpt.1385. Epub 2019 Mar 28. PMID: 30723889.
For more detailed press release, please click here.
To fully optimize the highly accurate, content-rich data generated from Novoheart’s mini-Heart Technology for detecting cardiac toxicity or efficacy, the Company has invested in developing machine learning capabilities to speed up the analysis of multiparametric drug screening data, enabling unbiased and automated drug classification. In doing so, it is able to facilitate new levels of automation and throughput in data analysis. This technology enables researchers to develop new and innovative ways for determining the effects of new as well as previously disregarded drugs on human subjects. The technology continues to advance and update as part of our software package for automation (Learn more details for the CTScreen ).
Lee EK, Tran DD, Keung W, Chan P, Wong G, Chan CW, Costa KD, Li RA, Khine M. Machine Learning of Human Pluripotent Stem Cell-Derived Engineered Cardiac Tissue Contractility for Automated Drug Classification. Stem Cell Reports. 2017 Nov 14;9(5):1560-1572. doi: 10.1016/j.stemcr.2017.09.008. Epub 2017 Oct 12. PMID: 29033305; PMCID: PMC5829317.
Friedreich’s ataxia (FRDA) is a hereditary neuromuscular degenerative disease that affects over 1 in 50,000 people worldwide. FRDA patients have a defective Frataxin gene, which often leads to lethal heart complications. In 2016, Novoheart teamed up with Pfizer’s Rare Disease Unit to generate a species-specific, functional in vitro experimental models of FRDA using our mini-Heart technology. The new disease models were created using genetically modified as well as FRDA patient-derived cells, capturing both electrical and mechanical defects of the heart observed in FRDA patients. This new approach marks an important step away from using animals as traditional testing models which have limited predictive ability for drug discovery due to dramatic differences in both the genetics and physiology.
In 2018, Novoheart filed a patent application based on our proprietary mini-Heart Platform of human bioengineered heart tissues to create disease models for ataxia affecting the heart. The disease models will benefit patients and drug developers by providing a unique and robust platform for testing candidate therapeutics.
Novoheart and Pfizer subsequently co-published the result of the study in 2019.
Wong AO, Wong G, Shen M, Chow MZ, Tse WW, Gurung B, Mak SY, Lieu DK, Costa KD, Chan CW, Martelli A, Nabhan JF, Li RA. Correlation between frataxin expression and contractility revealed by in vitro Friedreich’s ataxia cardiac tissue models engineered from human pluripotent stem cells. Stem Cell Res Ther. 2019 Jul 8;10(1):203. doi: 10.1186/s13287-019-1305-y. PMID: 31286988; PMCID: PMC6615274.
Relevant Press Releases:
Novoheart Files Patent Application on Disease Modelling Based on Landmark Research Conducted During Second Contract with Global Pharma Partner
Two new Pfizer-coauthored studies validate Novoheart’s pioneering human bioengineered heart tissues and chambers for improving drug development
Based on the scientific invention made in Dr. Roger Hajjar’s laboratory, AskBio was granted an IND approval for a novel gene therapy with a re-engineered vector designed to inhibit phosphatase activity in heart failure with reduced ejection fraction (HFrEF). After injecting 8 patients in the clinical trial, AskBio was subsequently sold to Bayer for $4billion USD in 2020. The same delivery method in Celladon’s first-in-man gene therapy trial (Learn more details in 2007) was also used in this trial.
Watanabe S, Ishikawa K, Fish K, Oh JG, Motloch LJ, Kohlbrenner E, Lee P, Xie C, Lee A, Liang L, Kho C, Leonardson L, McIntyre M, Wilson S, Samulski RJ, Kranias EG, Weber T, Akar FG, Hajjar RJ. Protein Phosphatase Inhibitor-1 Gene Therapy in a Swine Model of Nonischemic Heart Failure. J Am Coll Cardiol. 2017 Oct 3;70(14):1744-1756. doi: 10.1016/j.jacc.2017.08.013. PMID: 28958332; PMCID: PMC5807083.
Ishikawa K, Fish KM, Tilemann L, Rapti K, Aguero J, Santos-Gallego CG, Lee A, Karakikes I, Xie C, Akar FG, Shimada YJ, Gwathmey JK, Asokan A, McPhee S, Samulski J, Samulski RJ, Sigg DC, Weber T, Kranias EG, Hajjar RJ. Cardiac I-1c overexpression with reengineered AAV improves cardiac function in swine ischemic heart failure. Mol Ther. 2014 Dec;22(12):2038-2045. doi: 10.1038/mt.2014.127. Epub 2014 Jul 15. PMID: 25023328; PMCID: PMC4429688.
In 2014, Novoheart collaborated with Pfizer’s Global Safety Pharmacology Unit to systematically examine the pharmacological responses of engineered human ventricular-like Cardiac Tissue Strips (hvCTS) and Organoid Chambers (hvCOC) of the mini-Heart technology, to 25 cardioactive compounds covering various drug classes. We further quantified the predictive capacity of our mini-Heart technology in a blinded screening, with accuracies for negative, positive, and null inotropic effects at 100%, 86%, and 80%. Our healthy “human heart-in-a-jar” confirmed the results and further revealed that the more adult-like heart characteristics result in a greater sensitivity to positive inotropic drugs that stimulate cardiac contractility. The findings led to a two-tiered screening strategy that can provide an improved drug discovery approach to better predict clinical outcomes. Since the publication of this study in 2019, the accuracy for all 3 classes of inotropes have now reached 100%.
In 2014, Drs. Ronald Li and Kevin Costa reported the first human ventricular Cardiac Tissue Strip (hvCTS). This published study helped advance the field of human cardiac tissue engineering by examining 3D hvCTS created from enriched human embryonic stem cell-derived cardiomyocytes obtained using an efficient small molecule-mediated directed differentiation. Expanding the characterization of hvCTS using multiple complementary testing platforms, known drug responses were validated with natural human cardiac muscle. (Learn more details)
Turnbull IC, Karakikes I, Serrao GW, Backeris P, Lee JJ, Xie C, Senyei G, Gordon RE, Li RA, Akar FG, Hajjar RJ, Hulot JS, Costa KD. Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium. FASEB J. 2014 Feb;28(2):644-54. doi: 10.1096/fj.13-228007. Epub 2013 Oct 30. PMID: 24174427; PMCID: PMC3898643.
Drs. Ronald Li, Kevin Costa, and Michelle Khine co-founded Novoheart to transform the drug development process using bioartificial human heart prototypes created with state-of-the-art stem cell and bioengineering approaches.
In 2006, Dr. Ronald Li’s group at Johns Hopkins published a series of studies which employed a complementary set of stem cell and gene transfer technologies to construct a biological pacemaker, that was tested in rats, guinea pigs and subsequently side-by-side with electronic pacemakers in mini-pigs. The study won American Heart Association’s Ground-breaking Study of the Year in 2006, and was highlighted in an editorial commentary by Harvard scientists. This effort evolved and a related NIH grant subsequently received a top 1% percentile ranking in the study section of Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA) in 2009, and formed the basis of Dr Li’s subsequent work in cardiac cell and tissue engineering.
Tse HF, Xue T, Lau CP, Siu CW, Wang K, Zhang QY, Tomaselli GF, Akar FG, Li RA. Bioartificial sinus node constructed via in vivo gene transfer of an engineered pacemaker HCN Channel reduces the dependence on electronic pacemaker in a sick-sinus syndrome model. Circulation. 2006 Sep 5;114(10):1000-11. doi: 10.1161/CIRCULATIONAHA.106.615385. Epub 2006 Aug 21. PMID: 16923751.
Cowan DB, McGowan FX Jr. A paradigm shift in cardiac pacing therapy? Circulation. 2006 Sep 5;114(10):986-8. doi: 10.1161/CIRCULATIONAHA.106.644799. PMID: 16952993; PMCID: PMC1570537.
Xue T, Siu CW, Lieu DK, Lau CP, Tse HF, Li RA. Mechanistic role of I(f) revealed by induction of ventricular automaticity by somatic gene transfer of gating-engineered pacemaker (HCN) channels. Circulation. 2007 Apr 10;115(14):1839-50. doi: 10.1161/CIRCULATIONAHA.106.659391. Epub 2007 Mar 26. PMID: 17389267; PMCID: PMC2698014.
Lieu DK, Chan YC, Lau CP, Tse HF, Siu CW, Li RA. Overexpression of HCN-encoded pacemaker current silences bioartificial pacemakers. Heart Rhythm. 2008 Sep;5(9):1310-7. doi: 10.1016/j.hrthm.2008.05.010. Epub 2008 May 15. PMID: 18693074.
Nattel S. Inward rectifier-funny current balance and spontaneous automaticity: cautionary notes for biologic pacemaker development. Heart Rhythm. 2008 Sep;5(9):1318-9. doi: 10.1016/j.hrthm.2008.06.014. Epub 2008 Jun 17. PMID: 18774109.
Siu CW, Lieu DK, Li RA. HCN-encoded pacemaker channels: from physiology and biophysics to bioengineering. J Membr Biol. 2006;214(3):115-22. doi: 10.1007/s00232-006-0881-9. Epub 2007 Jun 8. PMID: 17558529.
Chan PK, Li RA. Gene Delivery for the Generation of Bioartificial Pacemaker. Methods Mol Biol. 2017;1521:293-306. doi: 10.1007/978-1-4939-6588-5_21. PMID: 27910058.
Sun Y, Timofeyev V, Dennis A, Bektik E, Wan X, Laurita KR, Deschênes I, Li RA, Fu JD. A Singular Role of IK1 Promoting the Development of Cardiac Automaticity during Cardiomyocyte Differentiation by IK1 -Induced Activation of Pacemaker Current. Stem Cell Rev Rep. 2017 Oct;13(5):631-643. doi: 10.1007/s12015-017-9745-1. PMID: 28623610; PMCID: PMC5784831.
Chan YC, Siu CW, Lau YM, Lau CP, Li RA, Tse HF. Synergistic effects of inward rectifier (I) and pacemaker (I) currents on the induction of bioengineered cardiac automaticity. J Cardiovasc Electrophysiol. 2009 Sep;20(9):1048-54. doi: 10.1111/j.1540-8167.2009.01475.x. PMID: 19460073; PMCID: PMC2739246.
Lesso H, Li RA. Helical secondary structure of the external S3-S4 linker of pacemaker (HCN) channels revealed by site-dependent perturbations of activation phenotype. J Biol Chem. 2003 Jun 20;278(25):22290-7. doi: 10.1074/jbc.M302466200. Epub 2003 Mar 31. PMID: 12668666.
Tsang SY, Lesso H, Li RA. Dissecting the structural and functional roles of the S3-S4 linker of pacemaker (hyperpolarization-activated cyclic nucleotide-modulated) channels by systematic length alterations. J Biol Chem. 2004 Oct 15;279(42):43752-9. doi: 10.1074/jbc.M408747200. Epub 2004 Aug 8. PMID: 15299004.
In 2005, Dr. Roger Hajjar further developed the gene delivery technique and subsequently translated it to a pig model of heart failure, showing a reversal of cardiac dysfunction after intracoronary delivery (i.e., directly into the heart through the coronary arteries) of a recombinant adeno-associated virus (AAV). The success in the pig model, whose cardiovascular system is similar to human, formed the basis of the FDA-approved delivery protocol that Sardocor is using today for patients.
Hayase M, Del Monte F, Kawase Y, Macneill BD, McGregor J, Yoneyama R, Hoshino K, Tsuji T, De Grand AM, Gwathmey JK, Frangioni JV, Hajjar RJ. Catheter-based antegrade intracoronary viral gene delivery with coronary venous blockade. Am J Physiol Heart Circ Physiol. 2005 Jun;288(6):H2995-3000. doi: 10.1152/ajpheart.00703.2004. PMID: 15897329; PMCID: PMC1305914.
Kawase Y, Ly HQ, Prunier F, Lebeche D, Shi Y, Jin H, Hadri L, Yoneyama R, Hoshino K, Takewa Y, Sakata S, Peluso R, Zsebo K, Gwathmey JK, Tardif JC, Tanguay JF, Hajjar RJ. Reversal of cardiac dysfunction after long-term expression of SERCA2a by gene transfer in a pre-clinical model of heart failure. J Am Coll Cardiol. 2008 Mar 18;51(11):1112-9. doi: 10.1016/j.jacc.2007.12.014. PMID: 18342232.
In 2000, Dr. Ronald Li and his colleagues at Johns Hopkins University directly injected an engineered adenovirus carrying two genes, SERCA1a and Kir2.1, into the heart of the guinea pig heart to simultaneously modulate cardiac excitability and contractility. The study demonstrates the feasibility of using a dual gene therapy to correct contractile abnormalities and prevent arrhythmias.
Ennis IL, Li RA, Murphy AM, Marbán E, Nuss HB. Dual gene therapy with SERCA1 and Kir2.1 abbreviates excitation without suppressing contractility. J Clin Invest. 2002 Feb;109(3):393-400. doi: 10.1172/JCI13359. PMID: 11827999; PMCID: PMC150851.
Dr. Roger Hajjar’s laboratory demonstrated that cardiac myocytes isolated from human explanted hearts of cardiac transplant that were exhibiting depressed contractility can be rescued by increased SERCA2a activity either by gene transfer of SERCA2a or by decreasing phospholamban expression.
del Monte F, Harding SE, Schmidt U, Matsui T, Kang ZB, Dec GW, Gwathmey JK, Rosenzweig A, Hajjar RJ. Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a. Circulation. 1999 Dec 7;100(23):2308-11. doi: 10.1161/01.cir.100.23.2308. PMID: 10587333; PMCID: PMC1249502.
del Monte F, Harding SE, Dec GW, Gwathmey JK, Hajjar RJ. Targeting phospholamban by gene transfer in human heart failure. Circulation. 2002 Feb 26;105(8):904-7. doi: 10.1161/hc0802.105564. PMID: 11864915; PMCID: PMC1249505.
In 2018, Novoheart contracted with Amgen to further expand its current testing capabilities of the mini-Heart Technology by designing and developing a new versatile High-Throughput microplate which allows the screening of hundreds of drugs using engineered human ventricular Cardiac Tissue Strips (hvCTS). Termed the 96-well μCTS, the disposable microplate is a custom-designed plate with 96 “wells” used to simultaneously cultivate 96 individual miniature hvCTS. The first prototype of 96-well μCTS was completed in 2020. The Company is now continuing this work to develop a next-generation version of the 96-well μCTS to increase its compatibility with robotic plate handling and automated high-throughput screening technologies that have become industry-standard facilities in big pharma laboratories. (Learn more details for the CTScreen).
In 2008, inspired by the children’s toy Shrinky Dinks, Dr. Ronald Li and Dr. Michelle Khine co-invented a new micropatterning technology for systematically aligning human heart cells to reproduce their pattern in the native heart. This technology lays the foundation for the human ventricular Cardiac Anisotropic Sheet (hvCAS) (Learn more details for the mini-Organs Products). Dr. Khine’s inventions won her numerous honours including Innovators Under 35 by MIT Technology Review and Marie Claire Women on Top Award, and Fellow of the National Academy of Inventors.
Chen A, Lieu DK, Freschauf L, Lew V, Sharma H, Wang J, Nguyen D, Karakikes I, Hajjar RJ, Gopinathan A, Botvinick E, Fowlkes CC, Li RA, Khine M. Shrink-film configurable multiscale wrinkles for functional alignment of human embryonic stem cells and their cardiac derivatives. Adv Mater. 2011 Dec 22;23(48):5785-91. doi: 10.1002/adma.201103463. Epub 2011 Nov 8. PMID: 22065428.
Shum AM, Che H, Wong AO, Zhang C, Wu H, Chan CW, Costa K, Khine M, Kong CW, Li RA. A Micropatterned Human Pluripotent Stem Cell-Based Ventricular Cardiac Anisotropic Sheet for Visualizing Drug-Induced Arrhythmogenicity. Adv Mater. 2017 Jan;29(1). doi: 10.1002/adma.201602448. Epub 2016 Nov 2. PMID: 27805726.
Wang J, Chen A, Lieu DK, Karakikes I, Chen G, Keung W, Chan CW, Hajjar RJ, Costa KD, Khine M, Li RA. Effect of engineered anisotropy on the susceptibility of human pluripotent stem cell-derived ventricular cardiomyocytes to arrhythmias. Biomaterials. 2013 Nov;34(35):8878-86. doi: 10.1016/j.biomaterials.2013.07.039. Epub 2013 Aug 12. PMID: 23942210.
Luna JI, Ciriza J, Garcia-Ojeda ME, Kong M, Herren A, Lieu DK, Li RA, Fowlkes CC, Khine M, McCloskey KE. Multiscale biomimetic topography for the alignment of neonatal and embryonic stem cell-derived heart cells. Tissue Eng Part C Methods. 2011 May;17(5):579-88. doi: 10.1089/ten.TEC.2010.0410. Epub 2011 Feb 27. PMID: 21235325.
In 2007, Dr. Ronald Li’s team patented an invention for driving the maturation of stem cell-derived human heart cells. Like a molecular time tunnel, this invention facilitates the use of these heart cells for drug screening and heart regeneration.
In 2014, the team patented another technology for driven maturation of stem cell-derived human heart cells without the need for genetic manipulation. These two inventions form the basis of our collaboration with Stanford University and AstraZeneca today.
Lieu DK, Fu JD, Chiamvimonvat N, Tung KC, McNerney GP, Huser T, Keller G, Kong CW, Li RA. Mechanism-based facilitated maturation of human pluripotent stem cell-derived cardiomyocytes. Circ Arrhythm Electrophysiol. 2013 Feb;6(1):191-201. doi: 10.1161/CIRCEP.111.973420. Epub 2013 Feb 7. PMID: 23392582; PMCID: PMC3757253.
Liu J, Lieu DK, Siu CW, Fu JD, Tse HF, Li RA. Facilitated maturation of Ca2+ handling properties of human embryonic stem cell-derived cardiomyocytes by calsequestrin expression. Am J Physiol Cell Physiol. 2009 Jul;297(1):C152-9. doi: 10.1152/ajpcell.00060.2009. Epub 2009 Apr 8. PMID: 19357236; PMCID: PMC2711646.
Other Related Publications:
Wong AO, Wong N, Geng L, Chow MZ, Lee EK, Wu H, Khine M, Kong CW, Costa KD, Keung W, Cheung YF, Li RA. Combinatorial Treatment of Human Cardiac Engineered Tissues With Biomimetic Cues Induces Functional Maturation as Revealed by Optical Mapping of Action Potentials and Calcium Transients. Front Physiol. 2020 Mar 12;11:165. doi: 10.3389/fphys.2020.00165. PMID: 32226389; PMCID: PMC7080659.
Zhang W, Kong CW, Tong MH, Chooi WH, Huang N, Li RA, Chan BP. Maturation of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) in 3D collagen matrix: Effects of niche cell supplementation and mechanical stimulation. Acta Biomater. 2017 Feb;49:204-217. doi: 10.1016/j.actbio.2016.11.058. Epub 2016 Nov 24. PMID: 27890729.
Keung W, Ren L, Sen Li, Wong AO, Chopra A, Kong CW, Tomaselli GF, Chen CS, Li RA. Non-cell autonomous cues for enhanced functionality of human embryonic stem cell-derived cardiomyocytes via maturation of sarcolemmal and mitochondrial KATP channels. Sci Rep. 2016 Sep 28;6:34154. doi: 10.1038/srep34154. PMID: 27677332; PMCID: PMC5039730.
Poon E, Keung W, Liang Y, Ramalingam R, Yan B, Zhang S, Chopra A, Moore J, Herren A, Lieu DK, Wong HS, Weng Z, Wong OT, Lam YW, Tomaselli GF, Chen C, Boheler KR, Li RA. Proteomic Analysis of Human Pluripotent Stem Cell-Derived, Fetal, and Adult Ventricular Cardiomyocytes Reveals Pathways Crucial for Cardiac Metabolism and Maturation. Circ Cardiovasc Genet. 2015 Jun;8(3):427-36. doi: 10.1161/CIRCGENETICS.114.000918. Epub 2015 Mar 10. PMID: 25759434.
Keung W, Boheler KR, Li RA. Developmental cues for the maturation of metabolic, electrophysiological and calcium handling properties of human pluripotent stem cell-derived cardiomyocytes. Stem Cell Res Ther. 2014 Jan 28;5(1):17. doi: 10.1186/scrt406. PMID: 24467782; PMCID: PMC4055054.
Medera’s human ventricular Cardiomyocytes (hvCMs) are terminally differentiated cardiomyocytes derived from human pluripotent stem cells (hPSCs) using Medera’s proprietary differentiation method. These cells have been extensively characterized for their electrophysiology, calcium homeostasis, transcriptome, microRNAome, and proteome.
They exhibit ventricular-like action potentials and express ventricular-specific myosin light chain MLC2v. With virtually homogeneous ventricular properties, these cells provide the consistency necessary to achieve reliable and reproducible results in downstream applications.
Yuan S, Yin X, Meng X, Chan JFW, Ye ZW, Riva L, et al. Clofazimine broadly inhibits coronaviruses including SARS-CoV-2. Nature. 593(7859):418-23.(2021)
Keung, W., Ren, L., Sen Li, Wong, A. O., Chopra, A., Kong, C. W., Tomaselli G. F., Chen, C. S., Li, R. A. Non-cell autonomous cues for enhanced functionality of human embryonic stem cell-derived cardiomyocytes via maturation of sarcolemmal and mitochondrial K(ATP) channels. Sci Rep. 6, 34154 (2016).
Poon, E., Keung, W., Liang, Y., Ramalingam, R., Yan, B., Zhang, S., Chopra, A., Moore, J., Herren, A., Lieu, D. K., Wong, H. S., Weng, Z., Wong, O. T., Lam, Y. W., Tomaselli, G. F., Chen, C., Boheler, K. R. & Li, R. A. Proteomic Analysis of Human Pluripotent Stem Cell-Derived, Fetal, and Adult Ventricular Cardiomyocytes Reveals Pathways Crucial for Cardiac Metabolism and Maturation. Circ Cardiovasc Genet 8, 427–436 (2015).
Zhang, S., Poon, E., Xie, D., Boheler, K. R., Li, R. A., Wong, H. S. Consensus comparative analysis of human embryonic stem cell-derived cardiomyocytes. PLoS One. 10, e0125442 (2015).
Karakikes I., Stillitano F., Nonnenmacher M., Tzimas C., Sanoudou D., Termglinchan V., Kong C. W., Rushing S., Hansen J., Ceholski D., Kolokathis F., Kremastinos D.,Katoulis A., Ren L., Cohen N., Gho J. M., Tsiapras D., Vink A., Wu J. C., Asselbergs F. W., Li R. A., Hulot J. S., Kranias E. G., Hajjar R. J. Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy. Nat Commun. 6, 6955 (2015).
Chen, G., Li, S., Karakikes, I., Ren, L., Chow, M. Z., Chopra, A., Keung, W., Yan, B., Chan, C. W., Costa, K. D., Kong, C. W., Hajjar, R. J., Chen, C. S., Li, R. A. Phospholamban as a crucial determinant of the inotropic response of human pluripotent stem cell-derived ventricular cardiomyocytes and engineered 3-dimensional tissue constructs. Circ Arrthyhm Electrophysiol. 8, 193-201 (2015).
Li, R. A. Cardiovascular regeneration. Stem Cell Res Ther. 5, 141 (2014).
Weng, Z., Kong, C.-W., Ren, L., Karakikes, I., Geng, L., He, J., Chow, M. Z. Y., Mok, C. F., Chan, H. Y. S., Webb, S. E., Keung, W., Chow, H., Miller, A. L., Leung, A. Y. H., Hajjar, R. J., Li, R. A. & Chan, C. W. A simple, cost-effective but highly efficient system for deriving ventricular cardiomyocytes from human pluripotent stem cells. Stem Cells Dev. 23, 1704–1716 (2014).
Keung, W., Boheler, K. R., Li, R. A., Developmental cues for the maturation of metabolic, electrophysiological and calcium handling properties of human pluripotent stem cell-derived cardiomyocytes. Stem Cell Res Ther. 5, 17, (2014).
Karakikes, I., Senyel, G. D., Hansen, J., Kong, C.-W., Azeloglu, E. U., Stillitano, F., Lieu, D. K., Wang, J., Ren, L., Hulot, J.-S., Iyengar, R., Li, R. A. & Hajjar, R. j. Small molecule-mediated directed differentiation of human embryonic stem cells toward ventricular cardiomyocytes. Stem Cells Transl. Med. 3, 18–31 (2014).
Li, S., Cheng, H., Tomaselli, G. F., Li, R. A. Mechanistic basis of excitation-contraction coupling in human pluripotent stem cell-derived ventricular cardiomyocytes revealed by Ca2+ spark characteristics: direct evidence of functional Ca2+-induced Ca2+ release. Heart Rhythm. 11, 133-140 (2014).
Li, S., Chen, G., Li, R. A. Calcium signalling of human pluripotent stem cell-derived cardiomyocytes. J Physiol. 591, 5279-5290 (2013).
Poon, E., Yan, B., Zhang, S., Rushing, S., Keung, W., Ren, L., Lieu, D. K., Geng, L., Kong, C. W., Wang, J., Wong H. S., Boheler, K. R., Li, R. A. Transcriptome-guided functional analyses reveal novel biological properties and regulatory hierarchy of human embryonic stem cell-derived ventricular cardiomyocytes crucial for maturation. PLoS One. 8, e77784 (2013).
Chow, M. Z., Geng, L., Kong, C. W., Keung, W., Fung, J. C., Boheler, K. R., Li, R. A. Epigenetic regulation of the electrophysiological phenotype of human embryonic stem cell-derived ventricular cardiomyocytes: insights for driven maturation and hypertrophic growth. Stem Cells Dev. 22, 2678-2690 (2013).
Chow, M., Boheler, K. R., Li, R. A. Human pluripotent stem cell-derived cardiomyocytes for heart regeneration, drug discovery and disease modelling: from the genetic, epigenetic, and tissue modeling perspective. Stem Cell Res Ther. 4, 97 (2013).
Lieu, D. K., Fu, J. D., Chiamvimonvat, N., Tung, K. C., McNerney, G. P., Huser, T., Keller, G., Kong, C. W., Li, R. A. Mechanism-based facilitated maturation of human pluripotent stem cell-derived cardiomyocytes. Circ Arrhythm Electrophysiol. 6, 191-201 (2013).
Fu, J. D., Rushing, S. N., Lieu, D. K., Chan, C. W., Kong, C. W., Geng, L., Wilson, K. D., Chiamvimonvat, N., Boheler, K. R., Wu, J. C., Keller, G., Hajjar, R. J., Li, R. A. Distinct roles of microRNA-1 and -499 in ventricular specification and functional maturation of human embryonic stem cell-derived cardiomyocytes. PLoS One. 6, e27417 (2011).
Wilson, K. D., Hu, S., Venkatasubrahmanyam, S., Fu, J. D., Sun, N., Abilez, O. J., Baugh, J. J., Jia, F., Ghosh, Z., Li, R. A., Butte, A. J., Wu, J. C. Dynamic microRNA expression programs during cardiac differentiation of human embryonic stem cells: role for miR-499. Circ Cardiovasc Genet. 3, 426-435 (2010).
Fu, J. D., Jiang, P., Rushing, S., Liu, J., Chiamvimonvat, N., Li, R. A. Na+/Ca2+ exchanger is a determinant of excitation-contraction coupling in human embryonic stem cell-derived ventricular cardiomyocytes. Stem Cells Dev. 19, 773-782 (2010).
Liu, J., Lieu, D. K., Siu, C. W., Fu, J. D., Tse, H. F., Li, R. A. Facilitated maturation of Ca2+ handling properties of human embryonic stem cell-derived cardiomyocytes by calsequestrin expression. Am J Physiol Cell Physiol. 297, C152-159 (2009).
Lieu, D. K., Liu, J., Siu, C. W., McNerney, G. P., Tse, H. F., Abu-Khalil, A., Huser, T., Li, R. A. Absence of transverse tubules contributes to non-uniform Ca(2+) wavefronts in mouse and human embryonic stem cell-derived cardiomyocytes. Stem Cells Dev. 18, 1493-1500 (2009).
Chan, J. W., Lieu, D. K., Huser, T., Li, R. A. Label-free separation of human embryonic stem cells and their cardiac derivatives using Raman spectroscopy. Anal Cham. 81, 1324-1331 (2009).
Liu J., Fu J. D., Siu C. W., Li R. A. Functional sarcoplasmic reticulum for calcium handling of human embryonic stem cell-derived cardiomyocytes: insights for driven maturation. Stem Cells. 12, 3038-44 (2007).
Wang K., Xue T., Tsang S. Y., Van Huizen R., Wong C. W., Lai K. W., Ye Z., Cheng L., Au K. W., Zhang J., Li G. R., Lau C. P., Tse H. F., Li R. A. Electrophysiological properties of pluripotent human and mouse embryonic stem cells. Stem Cells. 10, 1526-34 (2005).
Contractile performance is an essential function of the human heart, yet conventional 2-D cardiomyocyte cultures are inadequate for assessing contractility as they cannot perform physiological contractions on rigid plasticware. Tissue engineering offers a superior contractile assay in the form of Medera’s human ventricular Cardiac Tissue Strip (hvCTS), which is structurally and functionally similar to native trabecular muscle. This assay consists of aligned hvCMs in 3-D hydrogel mixture that is constructed using Medera’s custom-designed bioreactor with integrated force-sensing posts at the ends. This model has been validated as a sensitive and reliable predictor of clinical effects of drugs or pathologies on cardiac contractility.
Wong AOT, Gurung B, Wong WS, Mak SY, Tse WW, Li CM, et al. Adverse effects of hydroxychloroquine and azithromycin on contractility and arrhythmogenicity revealed by human engineered cardiac tissues. Journal of Molecular and Cellular Cardiology. 153:106-10.
Wong AOT, Wong G, Shen M, Chow MZY, Tse WW, Gurung B, et al. Correlation between frataxin expression and contractility revealed by in vitro Friedreich’s ataxia cardiac tissue models engineered from human pluripotent stem cells. Stem Cell Research and Therapy. 10(1):203.(2019)
Keung W, Chan PKW, Backeris PC, Lee EK, Wong N, Wong AOT, et al. Human Cardiac Ventricular-Like Organoid Chambers and Tissue Strips From Pluripotent Stem Cells as a Two-Tiered Assay for Inotropic Responses. Clinical Pharmacology and Therapeutics. 106(2):402-14.(2019)
Lee, E. K., Tran, D. D., Keung, W., Chan, P., Wong, G., Chan, C. W., Costa, K. D., Li, R. A. & Khine, M. Machine Learning of Human Pluripotent Stem Cell-derived Engineered Cardiac Tissue Contractility for Automated Drug Classification. Stem Cell Reports. 9, 1560-1572 (2017).
Mayourian J., Cashman T. J., Ceholski D. K., Johnson B. V., Sachs D., Kaji D. A., Sahoo S., Hare J. M., Hajjar R. J., Sobie E. A., Costa K. D. Experimental and Computational Insight Into Human Mesenchymal Stem Cell Paracrine Signaling and Heterocellular Coupling Effects on Cardiac Contractility and Arrhythmogenicity. Circ Res. 121, 411-423 (2017).
Zhang, W., Kong, C. W., Tong, M. H., Chooi, W. H., Huang, N., Li, R. A., Chan, B. P. Maturation of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) in 3D collagen matrix: Effects of niche cell supplementation and mechanical stimulation. Acta Biomater. 49, 204-217 (2017).
Stillitano F., Turnbull I. C., Karakikes I., Nonnenmacher M., Backeris P., Hulot J. S., Kranias E. G., Hajjar R. J., Costa K. D. Genomic correction of familial cardiomyopathy in human engineered cardiac tissues. Eur Heart J. 37, 3282-3284 (2016).
Keung, W., Ren, L., Sen Li, Wong, A. O., Chopra, A., Kong, C. W., Tomaselli, G. F., Chen, C. S., Li, R. A. Non-cell autonomous cues for enhanced functionality of human embryonic stem cell-derived cardiomyocytes via maturation of sarcolemmal and mitochrondrial K(ATP) channels. Sci Rep. 6, 34154 (2016).
Cashman, T. J., Josowitz, R., Gelb, B. D., Li, R. A., Dubois, N. C., Costa, K. D., Construction of Defined Human Engineered Cardiac Tissues to Study Mechanisms of Cardiac Cell Therapy. J Vis Exp. 109, e53447 (2016).
Cashman, T. J., Josowitz, R., Johnson, B. V, Gelb, B. D. & Costa, K. D. Human Engineered Cardiac Tissues Created Using Induced Pluripotent Stem Cells Reveal Functional Characteristics of BRAF-Mediated Hypertrophic Cardiomyopathy. PLoS One 1–17 (2016).
Karakikes, I., Stillitano, F., Nonnenmacher, M., Tzimas, C., Sanoudou, D., Termglinchan, V., Kong, C. W., Rushing, S., Hansen, J., Ceholski, D., Kolokathis, F., Kremastinos, D., Katoulis, A., Ren, L., Cohen, N., Gho, J. M., Tsiapras, D., Vink, A., Wu, J. C., Asselbergs, F. W., Li, R. A., Hulot, J. S., Kranias, E. G., Hajjar, R. J. Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy. Nat Commun. 6, 6955 (2015).
Chen, G., Li, S., Karakikes, I., Ren, L., Chow, M. Z., Chopra, A., Keung, W., Yan, B., Chan, C. W. Y., Costa, K. D., Kong, C., Hajjar, R. J., Chen, C. S. & Li, R. A. Phospholamban as a crucial determinant of the inotropic response of human pluripotent stem cell–derived ventricular cardiomyocytes and engineered 3-dimensional tissue constructs. Circ Arrhythm Electrophysiol 8, 193–202 (2015).
Turnbull, I. C., Karakikes, I., Serrao, G. W., Backeris, P., Lee, J. J., Xie, C., Senyei, G., Gordon, R. E., Li, R. A., Akar, F. G., Hajjar, R. J., Hulot, J. & Costa, K. D. Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium. FASEBJ. 28, 644–654 (2014).
Serrao, G. W., Turnbull, I. C., Ancukiewicz, D., Kim, D. E., Kao, E., Cashman, T. J., Hadri, L., Hajjar, R. J. & Costa, K. D. Myocyte-depleted engineered cardiac tissues support therapeutic potential of mesenchymal stem cells. Tissue Eng. Part A 18, 1322–1333 (2012).
Effective modelling of arrhythmias in vitro is challenging: by definition they are multicellular events that can only be recorded by monitoring conduction patterns in electrically coupled cardiomyocytes. Conventional assays can only use surrogate markers for arrhythmia: the hERG assay, standard in the industry, for example, uses inhibition of a single potassium channel exogenously expressed in non-cardiac cell lines as an indicator for proarrhythmic risk. Although these remain the standard tests for arrhythmogenicity, global drug regulators recognize their pitfalls and are actively seeking better alternatives, notably in the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative of the FDA. Human pluripotent stem cell-derived cardiomyocytes are inherently prone to arrhythmic events when cultured as randomly oriented monolayers. Medera’s human ventricular Cardiac Anisotropic Sheet (hvCAS) assay utilizes specially designed microgrooved substrates that physically guide hvCMs to align in a similar manner to that in the native human ventricle. The aligned cells show anisotropic electrical conduction which has been validated to reduce the baseline arrhythmogenicity compared to monolayers without a cardiomimetic preferential conduction axis.
Shum, A. M. Y., Che, H., Wong, A. O., Zhang, C., Wu, H., Chan, C. W. Y., Costa, K., Khine, M., Kong, C. & Li, R. A. A Micropatterned Human Pluripotent Stem Cell-Based Ventricular Cardiac Anisotropic Sheet for Visualizing Drug-Induced Arrhythmogenicity. Adv Mater. 29, (2017).
Chen, A., Lee, E., Tu, R., Santiago, K., Grosberg, A., Fowlkes, C. & Khine, M. Integrated platform for functional monitoring of biomimetic heart sheets derived from human pluripotent stem cells. Biomaterials 35, 675–83 (2014).
Wang, J., Chen, A., Lieu, D. K., Karakikes, I., Chen, G., Keung, W., Chan, C. W., Hajjar, R. J., Costa, K. D., Khine, M. & Li, R. A. Effect of engineered anisotropy on the susceptibility of human pluripotent stem cell-derived ventricular cardiomyocytes to arrhythmias. Biomaterials 34, 8878–8886 (2013).
Chen, A., Lieu, D. K., Freschauf, L., Lew, V., Sharma, H., Wang, J., Nguyen, D., Karakikes, I., Hajjar, R. J., Gopinathan, A., Botvinick, E., Fowlkes, C. C., Li, R. A. & Khine, M. Shrink-film configurable multiscale wrinkles for functional alignment of human embryonic stem cells and their cardiac derivatives. Adv. Mater. 23, 5785–91 (2011).
Luna, J. I., Ciriza, J., Garcia-ojeda, M. E., Kong, M., Herren, A., Lieu, D. K., Li, R. A., Fowlkes, C. C., Khine, M. & McCloskey, K. E. Multiscale biomimetic topography for the alignment of neonatal and embryonic stem cell-derived heart cells. Tissue Eng. Part C Methods 17, 579–588 (2011).
Xue, T., Cho, H. C., Akar, F. G., Tsang, S. Y., Jones, S. P., Marbán, E., Tomaselli, G. F., Li, R. A. Functional integration of electrically active cardiac derivatives from genetically engineered human embryonic stem cells with quiescent recipient ventricular cardiomyocytes: insights into the development of cell-based pacemakers. Circulation. 111, 11-20 (2005).
Medera’s fluid-ejecting 3-D human ventricular Cardiac Organoid Chamber (hvCOC), a.k.a. “human heart-in-a-jar” is the only technology available to date that enables the clinically informative assessment of human cardiac pump performance which no other human engineered heart tissues on the market are capable of. Combined with complementary custom-designed hardware and software, the best-in-class “human heart-in-a-jar” allows drug screening and disease modelling with unprecedented biofidelity.
Li, R. A., Keung, W., Cashman, T. J., Backeris, P. C., Chow, M. Z., Johnson, B. V., Bardot, E. S., Wong, A. O. T., Chan, P. K. W., Chan, C. W. Y., Costa K. D. Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells. Biomaterials. 163, 116-127 (2018).
Lee, E. J., Kim, D. E., Azeloglu, E. U. & Costa, K. D. Engineered cardiac organoid chambers: toward a functional biological model ventricle. Tissue Eng. Part A 14, 215–25 (2008).
In 2021, an open IND is granted from the FDA for Sardocor to start gene therapy clinical trials for Heart Failure with reduced Ejection Fraction (HFrEF) and preserved Ejection Fraction (HFpEF) in the US.
Sardocor’s HFpEF gene therapy trial will be the first-in-class.
The first patient with severe HFrEF was injected by intracoronary means with Medera’s first gene therapy drug SRD-001/2 in Dec 2021. As of April 2022, there have been no adverse events or safety concerns, as assessed by the Safety Committee.
Novoheart was named a 2020 Venture 50 Company, ranked among the TSX Venture Exchange’s top 50 best performing companies.
The ranking comprises ten companies from each of five key industry sectors. Novoheart is one of the ten best performers within the Clear Technology and Life Sciences sector.
Ranking was based on three equally weighted criteria:
There are two main types of heart failure – Heart Failure with reduced Ejection Fraction (HFrEF) and Heart Failure with preserved Ejection Fraction (HFpEF) which accounts for roughly half of all new cases of heart failure. In recent years, new therapies have been introduced for HFrEF which reduce deaths and hospitalization due to the disease. But these drugs do not work as well in HFpEF. Research is much needed to identify alternative strategies for treating HFpEF, and reliable animal models of the disease are lacking. To achieve this goal, Novoheart has teamed up with AstraZeneca to build preclinical human models of HFpEF designed to understand the disease mechanism, and predict the effects of potential medicines, bringing the most promising agents into clinical trials. This in vitro model builds on Novoheart’s heart-in-a-jar from the mini-Heart technology and will be used to test new therapies.
In 2019, Novoheart announced an exclusive licensing agreement with Harvard University’s Office of Technology Development to combine its state-of-the-art mini-Heart Platform with Harvard’s pioneering tissue-engineered scale model of the heart ventricle and related bioreactor technology. By integrating Harvard’s valved bioreactor technology with Novoheart’s proprietary human heart-in-a-jar, Novoheart will advance its disease modelling capabilities including modelling of highly prevalent heart diseases such as dilated cardiomyopathy and hypertrophic cardiomyopathy, for improved discovery of new therapeutics targeting such diseases.
Novoheart was selected as one of “The Top 50 of Innovative Biotechnology Enterprises in Guangdong-Hong Kong-Macau Greater Bay Area 2018”, as one of 5 enterprises from Hong Kong on the list.
The award ceremony was held in Guangzhou on September 7, 2018. The selection is co-organized by ZDVC Research, KPMG China and the Guangdong Medical Valley. The selection process lasted for three months, led by a panel of advisors from government agencies, third-party research organizations, professional investment entities and medical institutions.
Novoheart Holdings Inc., was listed in Canada on TSX Venture Exchange (NVH:V) on October 3, 2017. The company announced its dual listing in Germany on Tradegate Exchange under ticker 3NH (ISIN: CA67011V1076) on October 18, 2017.
Drs. Kevin Costa and Roger Hajjar published a study in the European Heart Journal demonstrating for the first time that gene editing to correct the PLN-R14del mutation in iPSCs from patients carrying this variant of the phopholamban gene was able to restore contractile function of engineered cardiac tissue strips to match tissues from healthy donors. This could lead to new gene therapy strategies for these patients who suffer severe and early onset dilated and arrhythmogenic cardiomyopathy.
Stillitano F, Turnbull IC, Karakikes I, Nonnenmacher M, Backeris P, Hulot JS, Kranias EG, Hajjar RJ, Costa KD. Genomic correction of familial cardiomyopathy in human engineered cardiac tissues. Eur Heart J. 2016 Nov 14;37(43):3282-3284. doi: 10.1093/eurheartj/ehw307. Epub 2016 Jul 22. PMID: 27450564; PMCID: PMC6425468.
In 2015, the first human “heart-in-a-jar” was successfully created and measured in the Li and Costa Labs. This ground-breaking technology received much attention from global news media, including BBC World, Bloomberg, CNBC etc. To this day, Novoheart remains the only company on the market with the “human heart-in-a-jar” technology.
Li RA, Keung W, Cashman TJ, Backeris PC, Johnson BV, Bardot ES, Wong AOT, Chan PKW, Chan CWY, Costa KD. Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells. Biomaterials. 2018 May;163:116-127. doi: 10.1016/j.biomaterials.2018.02.024. Epub 2018 Feb 10. PMID: 29459321; PMCID: PMC6561506.
By combining the joint expertise of Drs. Ronald Li and Kevin Costa in cell and tissue engineering, and electrophysiology and mechanobiology, respectively, and after 4 years of effort, the world’s first human mini-heart prototype was successfully created and tested. The scientific work was published in 2015. (Learn more details in 2015)
In 2010, Dr. Kevin Costa began his research in creating engineered cardiac tissues with rat neonatal ventricular cardiomyocytes. In 2012, he reported these results together with a system that was created to examine the contractile function of these rat cell-derived Engineered Cardiac Tissues (ECTs), a precursor to human ventricular Cardiac Tissue Strip (hvCTS). (Learn more details in 2014)
Serrao GW, Turnbull IC, Ancukiewicz D, Kim DE, Kao E, Cashman TJ, Hadri L, Hajjar RJ, Costa KD. Myocyte-depleted engineered cardiac tissues support therapeutic potential of mesenchymal stem cells. Tissue Eng Part A. 2012 Jul;18(13-14):1322-33. doi: 10.1089/ten.TEA.2011.0278. Epub 2012 Jun 25. PMID: 22500611; PMCID: PMC3397121.
At Columbia University, Dr. Kevin Costa embarked on the development of a rat mini-heart. In 2007, he was awarded funding from the National Institutes of Health (NIH) in the US as the top 1% percentile ranked grant of the year. In 2008, he published on the first-generation rat mini-heart, a precursor to the human “heart-in-a-jar”. A year later, he started collaborating with Dr. Ronald Li to design the world’s first human “heart-in-a-jar” by combining their expertise in cardiac cell and tissue engineering, mechanobiology, electrophysiology and human stem cell derived cardiomyocytes. (Learn more details in 2015)
Lee EJ, Kim DE, Azeloglu EU, Costa KD. Engineered cardiac organoid chambers: toward a functional biological model ventricle. Tissue Eng Part A. 2008 Feb;14(2):215-25. doi: 10.1089/tea.2007.0351. PMID: 18333774.
Using the delivery technique invented by Dr. Roger Hajjar at Massachusetts General Hospital/Harvard (Learn more details in 1997), Celladon obtained a US FDA approval in 2007 to launch the world’s first-in-man gene therapy trial to target heart failure by directly injecting an engineered adeno-associated virus (AAV) containing the SERCA gene into the coronary arteries. Having been used by Celladon, Asklepios Biopharmaceutical (AskBio, which was later acquired by Bayer), (Learn more details in 2016) and Sardocor, this delivery method has been proven both safe and effective in human.
Hajjar RJ, Zsebo K, Deckelbaum L, Thompson C, Rudy J, Yaroshinsky A, Ly H, Kawase Y, Wagner K, Borow K, Jaski B, London B, Greenberg B, Pauly DF, Patten R, Starling R, Mancini D, Jessup M. Design of a phase 1/2 trial of intracoronary administration of AAV1/SERCA2a in patients with heart failure. J Card Fail. 2008 Jun;14(5):355-67. doi: 10.1016/j.cardfail.2008.02.005. Epub 2008 May 27. PMID: 18514926.
Jaski BE, Jessup ML, Mancini DM, Cappola TP, Pauly DF, Greenberg B, Borow K, Dittrich H, Zsebo KM, Hajjar RJ; Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease (CUPID) Trial Investigators. Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial. J Card Fail. 2009 Apr;15(3):171-81. doi: 10.1016/j.cardfail.2009.01.013. PMID: 19327618; PMCID: PMC2752875.
Jessup M, Greenberg B, Mancini D, Cappola T, Pauly DF, Jaski B, Yaroshinsky A, Zsebo KM, Dittrich H, Hajjar RJ; Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) Investigators. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure. Circulation. 2011 Jul 19;124(3):304-13. doi: 10.1161/CIRCULATIONAHA.111.022889. Epub 2011 Jun 27. PMID: 21709064; PMCID: PMC5843948.
Zsebo K, Yaroshinsky A, Rudy JJ, Wagner K, Greenberg B, Jessup M, Hajjar RJ. Long-term effects of AAV1/SERCA2a gene transfer in patients with severe heart failure: analysis of recurrent cardiovascular events and mortality. Circ Res. 2014 Jan 3;114(1):101-8. doi: 10.1161/CIRCRESAHA.113.302421. Epub 2013 Sep 24. PMID: 24065463.
Celladon’s trial did not succeed to meet the clinical endpoints, however, because they were using doses, as allowed by FDA at the time, that were as much as 30-100X lower than what are typically used by today’s gene therapy companies. In general, the gene therapy field has advanced very significantly from the lessons learned in the past 20 or so years.
In the beginning of the Millennium, Dr. Ronald Li’s group at the Johns Hopkins University produced the world’s first genetically engineered human embryonic stem cells (hESC)-derived heart cells via lentivirus-mediated bioengineering. This was later awarded the American Heart Association’s Best Basic Study of the Year Award (2005). However, the efficiency of deriving heart cells from hESCs at the time was only 0.5%. This seminal report formed the basis for subsequent studies, including the first to discover the central importance of calcium handling in stem cell-derived cardiomyocyte function, the presence of ion channels in human pluripotent stem cells, the development of methods for mass production of cardiomyocytes, etc.
Xue T, Cho HC, Akar FG, Tsang SY, Jones SP, Marbán E, Tomaselli GF, Li RA. Functional integration of electrically active cardiac derivatives from genetically engineered human embryonic stem cells with quiescent recipient ventricular cardiomyocytes: insights into the development of cell-based pacemakers. Circulation. 2005 Jan 4;111(1):11-20. doi: 10.1161/01.CIR.0000151313.18547.A2. Epub 2004 Dec 20. PMID: 15611367.
Ion channels in human pluripotent stem cells
Wang K, Xue T, Tsang SY, Van Huizen R, Wong CW, Lai KW, Ye Z, Cheng L, Au KW, Zhang J, Li GR, Lau CP, Tse HF, Li RA. Electrophysiological properties of pluripotent human and mouse embryonic stem cells. Stem Cells. 2005 Nov-Dec;23(10):1526-34. doi: 10.1634/stemcells.2004-0299. Epub 2005 Aug 9. PMID: 16091557.
Jiang P, Rushing SN, Kong CW, Fu J, Lieu DK, Chan CW, Deng W, Li RA. Electrophysiological properties of human induced pluripotent stem cells. Am J Physiol Cell Physiol. 2010 Mar;298(3):C486-95. doi: 10.1152/ajpcell.00251.2009. Epub 2009 Dec 2. PMID: 19955484; PMCID: PMC2838581.
Mass production of cardiomyocytes
Karakikes I, Senyei GD, Hansen J, Kong CW, Azeloglu EU, Stillitano F, Lieu DK, Wang J, Ren L, Hulot JS, Iyengar R, Li RA, Hajjar RJ. Small molecule-mediated directed differentiation of human embryonic stem cells toward ventricular cardiomyocytes. Stem Cells Transl Med. 2014 Jan;3(1):18-31. doi: 10.5966/sctm.2013-0110. Epub 2013 Dec 9. PMID: 24324277; PMCID: PMC3902291.
Weng Z, Kong CW, Ren L, Karakikes I, Geng L, He J, Chow MZ, Mok CF, Chan HYS, Webb SE, Keung W, Chow H, Miller AL, Leung AY, Hajjar RJ, Li RA, Chan CW. A simple, cost-effective but highly efficient system for deriving ventricular cardiomyocytes from human pluripotent stem cells. Stem Cells Dev. 2014 Jul 15;23(14):1704-16. doi: 10.1089/scd.2013.0509. Epub 2014 Apr 22. Erratum in: Stem Cells Dev. 2016 Jun 1;25(11):882. PMID: 24564569; PMCID: PMC4086679.
Calcium handling of human pluripotent stem cell-derived cardiomyocytes
Liu J, Fu JD, Siu CW, Li RA. Functional sarcoplasmic reticulum for calcium handling of human embryonic stem cell-derived cardiomyocytes: insights for driven maturation. Stem Cells. 2007 Dec;25(12):3038-44. doi: 10.1634/stemcells.2007-0549. Epub 2007 Sep 13. PMID: 17872499.
Li S, Cheng H, Tomaselli GF, Li RA. Mechanistic basis of excitation-contraction coupling in human pluripotent stem cell-derived ventricular cardiomyocytes revealed by Ca2+ spark characteristics: direct evidence of functional Ca2+-induced Ca2+ release. Heart Rhythm. 2014 Jan;11(1):133-40. doi: 10.1016/j.hrthm.2013.10.006. Epub 2013 Oct 3. PMID: 24096168.
Li S, Chopra A, Keung W, Chan CWY, Costa KD, Kong CW, Hajjar RJ, Chen CS, Li RA. Sarco/endoplasmic reticulum Ca2+-ATPase is a more effective calcium remover than sodium-calcium exchanger in human embryonic stem cell-derived cardiomyocytes. Am J Physiol Heart Circ Physiol. 2019 Nov 1;317(5):H1105-H1115. doi: 10.1152/ajpheart.00540.2018. Epub 2019 Jul 26. PMID: 31347915.
Li S, Chen G, Li RA. Calcium signalling of human pluripotent stem cell-derived cardiomyocytes. J Physiol. 2013 Nov 1;591(21):5279-90. doi: 10.1113/jphysiol.2013.256495. Epub 2013 Sep 9. PMID: 24018947; PMCID: PMC3936367.
At Harvard University, Dr. Roger Hajjar published his first study on gene therapy in 1997. Dr. Hajjar tested the effect of adenovirus-mediated transfer of the SERCA2a gene to modify calcium handling and contraction in isolated myocytes of a rat model of heart failure.
Hajjar RJ, Kang JX, Gwathmey JK, Rosenzweig A. Physiological effects of adenoviral gene transfer of sarcoplasmic reticulum calcium ATPase in isolated rat myocytes. Circulation. 1997 Jan 21;95(2):423-9. doi: 10.1161/01.cir.95.2.423. PMID: 9008460.
del Monte F, Williams E, Lebeche D, Schmidt U, Rosenzweig A, Gwathmey JK, Lewandowski ED, Hajjar RJ. Improvement in survival and cardiac metabolism after gene transfer of sarcoplasmic reticulum Ca(2+)-ATPase in a rat model of heart failure. Circulation. 2001 Sep 18;104(12):1424-9. doi: 10.1161/hc3601.095574. PMID: 11560860; PMCID: PMC1249503.
Miyamoto MI, del Monte F, Schmidt U, DiSalvo TS, Kang ZB, Matsui T, Guerrero JL, Gwathmey JK, Rosenzweig A, Hajjar RJ. Adenoviral gene transfer of SERCA2a improves left-ventricular function in aortic-banded rats in transition to heart failure. Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):793-8. doi: 10.1073/pnas.97.2.793. PMID: 10639159; PMCID: PMC15410.
Restenosis is when a part of the artery that was previously treated for blockage becomes narrow again.
Arteriovenous Fistula Failure occurs when the fistula surgically created for hemodialysis treatments is never usable or fails within the first three months of its use.
Pulmonary hypertension is high blood pressure in the blood vessels that supply the lungs (pulmonary arteries). It occurs when walls of the pulmonary arteries become thick and stiff, and cannot expand as well to allow blood through. The reduced blood flow makes it harder for the right side of the heart to pump blood through the arteries, causing damage to the right heart.
Pulmonary fibrosis means scarring in the lungs. Over time, the scar tissue blocks the movement of oxygen from inside the tiny air sacs in the lungs into the bloodstream, causing people who have pulmonary fibrosis to feel short of breath, particularly when walking and exercising.
Heart failure with preserved ejection fraction (HFpEF) is a form of heart failure with high left ventricular (LV) filling pressure despite normal or near normal LV ejection fraction.
Heart failure with reduced ejection fraction (HFrEF) occurs when the left ventricular ejection fraction (LVEF) is 40% or less and is accompanied by progressive left ventricular dilatation and adverse cardiac remodelling.
Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration and weakness due to the alterations of a protein called dystrophin that helps keep muscle cells intact.