“Phase 0” Clinical Trials In a Dish

Bringing a new drug to market is an incredibly long and expensive process that typically takes over a decade, costs billions of dollars, and has a 90% failure rate at the clinical trial stage of discovery. One of the biggest challenges is predicting whether a drug will be safe for people before the start of expensive clinical trials. In fact, nearly 30% of drugs fail in human trials because of unexpected side effects, including cognitive and neurological complications that may be the result of disruption or death of brain cells. A major reason for these failures is that current laboratory methods, which rely on animal models or a small number of human cell lines, do not adequately reflect the genetic diversity of real patient populations. In other words, because people differ biologically in many ways, a drug that is safe for some people may be toxic for others.

Can we use genetics to predict who can safely take a drug with minimal side effects?

To answer this question, we are using cell villages composed of neural cells from over one hundred different people to perform “Phase 0” clinical safety trials in a dish. We are simulating how drugs might behave in real-world populations by exposing these villages to different compounds—including chemotherapies and anti-epileptics—to see which individuals are most vulnerable to the toxic effects. We then analyze the genes and biological pathways that are activated differently between vulnerable and resistant individuals to uncover why some people are more sensitive than others. This knowledge could be instrumental to better understanding how our genetics influences drug response (known as pharmacogenomics).

If successful, our approach could help pharmaceutical companies identify dangerous drugs before they reach patients—or at the very least, know who may be ideal clinical trial participants based on their genetics—thus reducing the number of failed clinical trials and improving the safety of new treatments. Additionally, by discovering genetic markers that predict drug toxicity, we can work toward more personalized medicine—where doctors can use genetic tests to determine which drug is the safest and most effective for you, rather than pursuing the conventional trial-and-error route. Ultimately, this project aims to save lives and make medications safer for everyone by ensuring that drug safety testing accounts for the genetic diversity of real-world patients. Extensions of our approach that are aimed at improving the effectiveness of drugs are currently underway.