Constructing a library of custom-tailored human embryonic stem cell-derived cardiomyocytes for specific heart therapies

Funding Type: 
Comprehensive Grant
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

Malfunctions or significant loss of heart cells due to aging or diseases can lead to lethal consequences (e.g. heart attack, heart failure and various forms of irregular heart rhythms). Since heart cells normally lack the ability to regenerate, transplantation is the last resort for patients with end-stage heart failure. However, this option is severely limited by the number of donor organs available. Cell replacement therapy is an alternative for myocardial repair but is similarly hampered by the availability of transplantable cells (e.g. human fetal cardiomyocytes). Non-cardiac cells such as skeletal muscle myoblasts have thus been sought as alternatives, but potentially lethal side effects arise due to the fact that they are not genuine heart cells.

Human embryonic stem cells (hESCs), isolated from the inner cell mass of blastocysts, can self-renew and propagate indefinitely while maintaining their ability to become all cell types, including heart cells. Therefore, hESCs may provide an unlimited cell source. However, current methods for differentiating hESCs into specific heart cell types (e.g. pacemaker cells that are specialized for generating electrical heart rhythms, and cardiac atrial and ventricular muscles for the mechanical action of blood pumping) are stochastic. Furthermore, unlike the adult counterparts, hESC-derived CMs have embryonic-like properties. Indeed, some of these immature properties can even cause lethal electrical disturbances, making them unsafe for transplantation. Therefore, it is necessary to improve the yields of chamber-specific CMs and maturate their properties. Engineering of hESCs to create “custom-tailored” CMs can present a novel and flexible solution.

Using a combination of cell- and gene-based approaches, we have demonstrated, at the preclinical level, in both small (guinea pigs) and large (swines) animal disease models that the various biological alternatives that we developed are superior to such conventional treatments as device-based therapies (e.g. biological versus electronic pacemakers for sick sinus syndrome). These scientific progresses of ours have been reported by various public news media (e.g. WebMD, Forbes, etc). With such an established in-house platform, here we propose to employ a range of state-of-the-art scientific techniques that are uniquely available to us a) to construct a library of customized hESC-derived cardiomyocytes for specific heart therapies (e.g. pacemaker for rhythm generation disorders, and cardiac muscles for myocardial repair), and b) to test that cardiac function(s) of our animal disease models can be improved after transplantation of engineered hESC-derived cells. Collectively, this proposal serves to obtain a better understanding of the basic biology of hESC-derived heart cells, as well as to provide a unique translational platform for developing hESC-based heart therapies

Statement of Benefit to California: 

Human ESCs have been a hot topic because of their potential of curing numerous currently untreatable human diseases. The proposed project to be executed in CA has the following long-term visions: 1) to extend the human lifespan and to improve the quality of life via successful hESC research, 2) to provide a collegial and intellectually stimulating environment in CA for hESC research, 3) to make important, long half-life fundamental discoveries in the hESC field of high academic value, 4) to develop novel commercially-viable, therapeutic approaches that can directly benefit patients and our state's economy via translational hESC research, 5) to offer excellent training opportunities and education for the next-generation scientists, clinicians and academians. During the requested funding period, our specific mission is to build in CA a unique internationally renowned hESC research program that specializes in the proposed discipline. According to a recent article in 2006 (Nat. Biotech 24, 391), only a total of 132 hESC research articles from the entire medical literature were published during 1998-2004. To date, merely ~10 of all published hESC articles studied the heart and 5 were on ion channels and pumps. Clearly, such a low productivity in the fields of cardiovascular sciences and electrophysiology is not because they are less important than others. Instead, it reflects the associated technical difficulties. In fact, only 5 labs worldwide, including our own, have reported the successful derivation of heart cells from hESCs. In particular, we specifically focuses on genetic engineering of hESCs and their bioelectrical properties. This unique marriage (of hESC biology and quantitative sciences) enables us to employ a broad range of state-of-the-art techniques to investigate the focused topic of engineering hESC-derived heart cells. In fact, we have already gained the necessary momentum: 1) In the past year alone, we have filed in CA a total of 6 related patents. We have been approached by various companies {REDACTED} for potential licensing activities. 3) While the core science focuses on the heart, our experimental design and platform are highly scalable and of general utility to multiple disciplines. For instance, our efforts have led to preliminary data for supporting {REDACTED} other CIRM seed grants from our institution (c.f. Collaboration). Overall, we anticipate that our program will contribute to both the scholastic and economical developments in CA. This will be accomplished by training new stem cell scientists (for the academia and the biotech industry) and by creating new jobs (e.g. via extramural funding and licensing activities). Since our hESC work is not currently extramurally supported, receiving a comprehensive grant from CIRM is crucial for us to maintain our momentum, and to make further progresses for facilitating both basic discovery and translation.