One of the biggest challenges in drug discovery is the lack of predictive preclinical models for assessing drug efficacy and safety. Traditional 2D cell cultures and animal models frequently fail to replicate human physiology, resulting in high clinical trial failure rates, unexpected toxicity, and wasted resources. The need for human-relevant models has never been greater.
For these reasons, DefiniGEN has created Opti-HEP, a cutting-edge iPSC-derived hepatocyte model designed to overcome many of the drawbacks seen in animal and primary cell models. This innovative platform offers a highly predictive, scalable, and reproducible solution for preclinical drug testing, bridging the translational gap between early research and clinical success.
Why Traditional Cell Models Fall Short
Limitations of Animal Models
Animal testing has long been a standard in drug development, but it suffers from significant translational issues:
- Species Differences: Rodents and other animals have different metabolic pathways, making it difficult to predict human drug metabolism and toxicity.
- Poor Disease Representation: Many human conditions, such as metabolic-associated liver steatotic disease (MALSD) and cystic fibrosis-related liver disease (CFLD), do not naturally develop in animals.
- Ethical and Logistical Constraints: With growing regulatory pressure to reduce animal testing, new human-relevant models are essential.
Challenges with immortalized and primary cell models
Primary human hepatocytes are considered the gold standard for efficacy screening, while immortalized cell lines are cheaper and easier to culture. Nevertheless, there are drawbacks to both cell types, which have led researchers to seek alternative models.
- Lack of Functional Maturity: Immortalized hepatocyte lines lack key drug-metabolizing enzyme activity. This means that candidate compounds have not been properly screened, leading to inaccurate data being reported during screening investigations.
- Rapid Functional Decline: Primary hepatocytes lose function within days in culture, limiting their usefulness for long-term studies. This is a significant issue for researchers who are investigating compounds that require more than a few days to show an effect.
- Lack of availability: It is very challenging to isolate enough primary cells from patients for high-throughput screening investigations without batch-to-batch variation being present. This problem is even greater in cases where the patient suffers from a rare disease.
Why Traditional Models Fall Short
Limitations of Animal Models
Animal testing has long been a standard in drug development, but it suffers from significant translational issues:
- Species Differences: Rodents and other animals have different metabolic pathways, making it difficult to predict human drug metabolism and toxicity.
- Poor Disease Representation: Many human conditions, such as metabolic-associated liver steatotic disease (MALSD) and cystic fibrosis-related liver disease (CFLD), do not naturally develop in animals.
- Ethical and Logistical Constraints: With growing regulatory pressure to reduce animal testing, new human-relevant models are essential.
Challenges with immortalized and primary cell models
Primary human hepatocytes are considered the gold standard for efficacy screening, while immortalized cell lines are cheaper and easier to culture. Nevertheless, there are drawbacks to both cell types, which have led researchers to seek alternative models.
- Lack of Functional Maturity: Immortalized hepatocyte lines lack key drug-metabolizing enzyme activity. This means that candidate compounds have not been properly screened, leading to inaccurate data being reported during screening investigations.
- Rapid Functional Decline: Primary hepatocytes lose function within days in culture, limiting their usefulness for long-term studies. This is a significant issue for researchers who are investigating compounds that require more than a few days to show an effect.
- Lack of availability: It is very challenging to isolate enough primary cells from patients for high-throughput screening investigations without batch-to-batch variation being present. This problem is even greater in cases where the patient suffers from a rare disease.
How Opti-HEP is Revolutionizing Preclinical Testing
Opti-HEP offers a human-derived, highly functional and mature hepatocyte model that outperforms traditional preclinical systems. Here’s how:
Patient-Specific Drug Testing for Improved Efficacy
Opti-HEP are derived from induced pluripotent stem cells (iPSCs), meaning they can be generated from healthy or diseased individuals. This allows researchers to select a donor which is relevant to their research and perform downstream screening investigations while also generating as many hepatocytes as necessary for their screening investigation. Moreover, it reduces the need for animal models and allows for the study of genetic liver diseases, such as MASLD, Alpha-1 Antitrypsin Deficiency (A1ATD), Urea Cycle disorders, and Wilson’s Disease in a human model.
Enhanced Drug Metabolism and Toxicity Prediction
Opti-HEP closely resembles primary human hepatocytes in terms of functionality and outperform immortalized cell line since they express ASGR1, a key hepatocyte marker. Additionally, they offer numerous advantages over primary and immortalized cells, including:
- Consistent batch-to-batch reproducibility, eliminating donor-to-donor variability.
- Extended viability and functionality in culture for weeks instead of days, allowing for long-term drug testing for low clearance compounds.
- Scalability for high-throughput screening, making them ideal for pharmaceutical applications.
- Retained drug-metabolizing enzyme activity, enabling accurate CYP450-mediated metabolism and toxicity predictions. Furthermore, unlike immortalized cells, they demonstrate functional membrane localization and activity of ASGR1.
A New Era for Preclinical Liver Models
With its ability to mimic human liver function, accurately predict drug metabolism, and provide patient-specific insights, Opti-HEP is positioned as an invaluable preclinical liver model. By integrating this technology into drug discovery workflows, researchers can significantly reduce clinical trial failures, accelerate drug development, and improve patient safety.