Safety and efficacy are two critical components of getting a new drug approved, however demonstrating these factors can be difficult in some classes of drugs. Medications that affect cardiac tissue require high scrutiny, as both their potential benefits and risks to patients can be high. Novel lab-grown cardiomyocyte technology is shifting the way researchers identify and test drugs that impact the heart.
Evaluating the Cardiac Safety of Drug Candidates is Critical
When it comes to heart health, patient stakes are high and drug manufacturers carry a great liability risk. Assessing the safety of a candidate drug for cardiac health can be complicated, as dangerous side effects may appear in individuals with uncommon conditions that do not occur in healthy patients. This is particularly critical in patients at risk of developing arrhythmia or heartbeat abnormalities.
The figure below demonstrates how cardiac cells overexpressing a gene involved in potassium ion channels are more sensitive to the drug dofetilide than normal cells. Conditions like this are not always easy to test safety effects in clinical trials.
Capturing critical differences in how patients with existing arrhythmias or genetic predispositions to arrhythmia respond to a drug can be challenging in a standard clinical trial due to low numbers of individuals with a particular condition. However, identifying potential safety risks for these individuals protects both patients and drug manufacturers. Using predictive models of disease, like rodent trials and cell lines, can help identify potential interaction issues with a drug prior to use in humans.
Modeling Heart Disease is Complicated
While traditional and transgenic animal and cell models can provide a great deal of information about drug activity, it is often difficult to accurately replicate cardiac phenotypes in these systems. It can take multiple generations to create a transgenic mouse line for a specific disease or genetic condition and even well-matched lines often carry limitations due to differences in ionic currents between mice and humans.
Similarly, non-cardiac human cell lines that are commonly used in drug testing, like HEK cells, lack the unique features of heart cells that determine their behavior, particularly their electrophysiology. While these cell lines are able to assist researchers in determining general toxicity, they are not able to replicate conditions like arrhythmias or ion channel abnormalities that can lead to serious complications in heart tissue or help predict when a drug could benefit cardiac cells in a unique way.
Predicting the Effect of a New Drug Takes Precision
Along with safety testing, updated methods are necessary to help identify helpful drugs sooner. Clinical trials in humans are generally the last step in testing a drug. Prior to these trials a candidate drug needs to go through rounds of safety testing in lab-grown cell lines and laboratory animals. Since these systems do not always replicate effects in the human heart accurately, drug candidates with novel mechanisms that are human cardiac cell-specific may be overlooked or never make it to clinical trials.
Cultured Cardiomyocytes Offer a Novel Solution
The ideal solution to this problem is working with cultured human cardiomyocytes rather than animal or general non-cardiac cell lines. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM) are stem cells that have been collected from patients and programmed to differentiate into cardiomyocytes in the lab. These are true cardiac cells and can be used to test parameters that can only be measured in heart tissue, such as the capacity of a drug to induce arrhythmia.
Unlike in animal models, it is easy to develop hiPS-CM cell lines that express genetic abnormalities. Using lipid-based transfection protocols, researchers introduce mRNA from genes of interest into hiPS-CM cells. This causes the cells to behave as if they naturally express a mutation or disease condition associated with that gene. Researchers can then expose the transfected cardiomyocytes to drugs of interest and observe how their behavior and function are impacted. Using this methodology, the effect of a drug can be accurately predicted.
Developing Drugs for the Future
The technology utilized to develop and modify hiPS-CM cell lines can be leveraged throughout drug discovery and development to both assess how a drug impacts healthy cardiac cells and evaluate how it will interact with disease states and genetic abnormalities. This provides researchers with the ability to predict the potential of a new drug under multiple scenarios and identify risks for patients with unique physiologies.