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A new paradigm of personalized pharmacotherapy
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Current drug development is a lengthy, expensive process with an estimated duration of 12 years and capitalized cost of $1.8 billion. The high cost is largely due to late-stage attrition during drug development or safety issues discovered after drug introduction. On average, 23% of compounds fail to be approved after phase 3 trials and 4% of approved drugs are withdrawn.
An obvious solution to reducing drug development cost is earlier identification of potential efficacy and toxicity, before sunk costs occur. Shifting the attrition to earlier stages of drug development would significantly reduce development and other costs. Although the current paradigm of large clinical trials to determine efficacy is useful on a population level, it is not designed to provide treatment that is “personalized” to individual patients who have different traits (eg, genetic profiles).
However, it is now possible to identify the individual patient’s response to a drug ahead of time. By offering an in vitro platform that more closely resembles human cardiac tissue by recapitulating genetic and phenotypic properties of the somatic tissue donor, patient-specific human induced pluripotent stem cells (iPSCs) stand to revolutionize the field of drug development and create a new paradigm of personalized pharmacotherapy.
Karim Sallam
Joseph C. Wu
Human iPSCs are stem cells derived from somatic cells that are then artificially induced to develop pluripotency (ie, the ability to differentiate into all three germs layers and subsequent cells types). These cells are derived from patient tissues (eg, fibroblasts, peripheral blood mononuclear cells or adipocytes) and genetically modified using viral or non-viral methods. Human iPSCs have been differentiated into multiple cell lines, including neurons, hepatocytes and cardiomyocytes. Human iPSC-derived cardiomyocytes (iPSC-CMs) might provide an alternative source of tissue for cardiac regenerative therapy that avoids ethical issues associated with embryonic stem cells (ESCs). Moreover, iPSC-CMs offer advantages beyond regenerative therapy, making them a unique method of drug discovery, efficacy evaluation and toxicity screening. For example, by recapitulating the genetic profile and cellular phenotype of their donor, iPSC-CMs can be used to predict individualized responses to drug therapy.
Limited access
Drug discovery for primary cardiac disorders has been hampered by the lack of access to primary cardiac tissue. Our understanding of monogenic cardiac disorders has been accelerated by advances in next-generation sequencing methods, but our ability to study these disorders is still limited because current methods rely on surrogate animal models or scarce cardiac tissue. As an alternative, iPSC-CMs have the unique advantage of providing a virtually unlimited supply of in vitro cardiomyocytes that recapitulate the same genetic information as the tissue source. Thus, these cells provide an in vitro human model for monogenic disorders that could be studied by using detailed molecular techniques, which will better elucidate underlying mechanisms of these disorders and potentially lead to new drug targets.
Besides being amenable to detailed in vitro molecular analysis, iPSC-CMs provide a substrate that makes them suitable for phenotypic screening. IPSC-CMs spontaneously beat in monolayer enabling measurement of electrical data, ion channel currents and contractile force, which can provide a phenotypic measure of cell function. In addition, the relatively inexpensive and abundant supply of cardiomyocytes from the iPSC technology makes it possible for high-throughput screening (HTS) of compound libraries that may become novel drug therapies of various CVDs. Current toxicity testing relies on animal models and Chinese hamster ovarian (CHO) cells that overexpress cardiac channels, most commonly the human ether-a-go-go-related gene (hERG) channel. A recent study by our group confirmed that a library of patient-specific iPSC-CMs are indeed more reliable than conventional CHO cell method in predicting toxicity because iPSC-CMs provide a human model that more closely encompasses the complexities of human heart cells.
Currently, the gold standard for drug approval is to demonstrate efficacy on a population level compared with placebo or alternative therapy. For example, 15 patients with systolic dysfunction would need to be treated with a beta-blocker for one patient to derive a benefit. By contrast, the new paradigm of personalized medicine will allow the identification of which particular patient(s) in a group might actually stand to benefit the most from the therapy. Pharmacogenomics has yielded some results in this area, but clinical translation of this data has been limited; not surprising given the polygenetic nature of determinants of electrical and mechanical properties of cardiac cells. A major advantage of evaluating the phenotype of the cardiac cell rather than the genotype is the ability to encompass the aggregate response to all known and unknown genetic factors. To this end, iPSC-CMs offer an excellent means of evaluating phenotypic response as the cells recapitulate the genetic makeup of the source, thus enabling the phenotype response to be extrapolated to donor heart tissue.
Various approaches
There are multiple ways that iPSC-CMs can be used in personalized medicine. The most immediate approach is to prospectively test therapeutic efficacy or toxicity of drugs with high rates of toxicity or variable level of efficacy, such as antiarrhythmics. A more advanced concept is the “clinical trial in a dish” approach, in which a drug’s therapeutic efficacy can be measured during preclinical testing by using HTS of hundreds or thousands of patient-specific iPSC-CMs, potentially providing accurate extrapolations on efficacy and subgroup efficacy through such means.
As with any technology, there are limitations to the utility of iPSC-CMs in CV drug development. First, iPSC-CMs are relatively immature cardiomyocytes, resembling fetal cardiomyocytes more than adult cardiomyocytes; much research is under way in advancing the maturation of the cells. Furthermore, iPSC-CMs are an in vitro model and thus cannot recapitulate the complexities of in vivo cardiac physiology. Nonetheless, compared with genetically engineered CHO cells in vitro or rodent animal models in vivo, it is clear that iPSC-CM testing — even in its current form — has a valuable role to play in preclinical testing. Future refinements will make iPSC-CMs a much more versatile and powerful platform in the field.
In summary, iPSC-CMs now offer tremendous advantages as a robust in vitro model for understanding complex CV disorders and identifying new drug targets. Furthermore, they provide an excellent platform for testing efficacy and toxicity of cardiac and non-cardiac drugs. Lastly, by recapitulating the genetic profile of the person from which iPSCs are derived, these cardiomyocytes may capture all the genetic polymorphisms of the individual to better predict therapeutic response, providing a powerful new platform for personalized medicine.
Disclosure: Sallam reports no relevant financial disclosures. Wu has received funding from NIH, CIRM and AHA, and holds founding shares for Stem Cell Theranostics.