The human ether-à-go-go-related gene (hERG) got its name from the Ether-a-go-go (EAG) gene found in the fruit fly Drosophila melanogaster. The EAG gene was named in the 1960s by William D. Kaplan and William E. Trout, III, while at the City of Hope Hospital in Duarte, California. When flies with mutations in the EAG gene are anaesthetised with ether, their legs start to shake, like the dancing at the then popular Whisky a Go Go nightclub in West Hollywood, California.
The hERG gene is the human homolog of the fruitfully EAG gene. It encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (IKr), which is important for cardiac repolarization. The IKr channel is responsible for repolarizing the ventricles of the human heart after they contract. When the IKr channel is blocked, it can lead to a prolonged QT interval and an increased risk of torsades de pointes (see prior blog post for details on QT intervals).
The hERG gene is a druggable target. Drugs that block the hERG channel can be used to treat arrhythmias. However, these drugs also have the potential to prolong the QT interval and cause torsades de pointes. Therefore, it is important to carefully monitor patients who are taking drugs that block the hERG channel.
hERG assessments play a critical role in clinical drug development by evaluating the potential cardiac safety risks associated with new compounds. Dysfunctional hERG channels can lead to adverse effects, including potentially fatal arrhythmias. In this article, I discuss the significance of hERG assessments, their methodologies, and their impact on drug development.
Significance of hERG Assessments: hERG channels are responsible for repolarizing the heart's cells after each heartbeat. A drug's interaction with hERG channels can result in delayed cardiac repolarization, leading to a condition known as QT prolongation. This prolonged QT interval is associated with an increased risk of arrhythmias, notably Torsades de Pointes, a rare but life-threatening ventricular arrhythmia. Regulatory agencies, such as the FDA and EMA, require thorough hERG assessments to minimize the potential for adverse cardiac events.
Methodologies for hERG Assessments:
- Patch Clamp Assays: The gold standard for hERG assessment involves patch clamp assays, which directly measure the electrical currents passing through individual hERG channels. Automated high-throughput systems have improved the efficiency of this technique, allowing the evaluation of a wide range of compounds.
- Ion Flux Assays: These assays measure the flux of potassium ions across cell membranes expressing hERG channels. They offer quicker results and can be adapted to high-throughput screening.
- Computer Modeling: Computational models, such as quantitative structure-activity relationship (QSAR) models, predict a compound's interaction with hERG channels based on its chemical structure. While useful for early-stage screening, they may lack the accuracy of experimental methods.
Integration into Drug Development: hERG assessments are an integral part of the drug development process:
- Lead Optimization: During early stages of researching and identifying new drugs, compounds are tested for their potential to inhibit hERG channels. Medicinal chemists use these results to modify structures and minimize hERG-related risks while preserving therapeutic efficacy.
- Safety Pharmacology Studies: In-depth assessments are conducted on lead compounds, often using multiple methods. These studies aid in identifying compounds with acceptable hERG profiles for further development.
- Regulatory Submissions: Comprehensive hERG data is submitted to regulatory agencies as part of New Drug Applications (NDAs) or Marketing Authorization Applications (MAAs). A positive hERG profile contributes to a drug's overall safety profile.
Challenges and Future Directions: Despite advancements, challenges remain in accurately predicting a compound's proarrhythmic potential. Researchers are exploring more refined in vitro models that better replicate human cardiac tissue. Combining hERG assessments with other cardiac safety markers, like action potential assays, may enhance overall predictive capabilities.
hERG assessments are indispensable in assessing the cardiac safety risks of new drugs. The ability to accurately predict a compound's impact on hERG channels is crucial in avoiding potentially life-threatening arrhythmias. Employing a combination of experimental assays and computational models, drug developers strive to strike a balance between therapeutic efficacy and cardiac safety.
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