Exploring Mitochondrial Function
Mitochondrial bioenergetic balance may be a pertinent marker for early preclinical safety testing, especially in predicting DILI, according to Nathalie Compagnone, Ph.D., founder and CEO of Innovative Concepts in Drug Development (ICDD). Mitochondria are central to drug development as targets in CNS diseases, cancer, and metabolic diseases and as one of the main off-target sites causing undesirable side effects and toxicity. Dr. Compagnone’s team has developed a cell-based high-throughput screening (HTS) methodology to investigate the mechanisms underlying DILI and cardiac toxicity.
The Mitosafe® technology developed at ICDD engages multiple integrated mitochondrial targets and the interactions are modeled. The functional bioassays reflect bioenergetic balance and redox status, and reveal mitochondrial DNA depletion, among other parameters.
The Mitostream® technology engages multiple integrated cellular targets, with the interactions modeled via measurement of mitochondrial behavior. The technology measures the quantitative and qualitative levels of cellular adaptation, drug toxicity and sensitivity profiles, and disease signatures. “Mitosafe is for early deselection of hits using a mechanistic approach, and Mitostream is for anticipation of lead/candidate clinical tolerance,” said Dr. Compagnone.
Dr. Compagnone and her team have developed a bioenergetic balanced screen (BBS) for fast, affordable, and efficient early toxicity testing by measuring the oxygen consumption rate, ATP levels, lactose production, and cell viability in live, nonpermeabilized cells. It identifies modulators of mitochondrial oxidative phosphorylation and glycolysis leading to ATP synthesis. It is used in identifying and validating a functional readout in HTS format that can be used as a marker to screen early compounds with potential toxicity, at dosages relevant to the clinical setting, she claimed.
“Our bioassays tend to reduce the bias commonly used in measuring cytotoxicity by assessing pharmacological effects at clinically relevant doses leading to mitochondrial dysfunction, an early step of hepato- and cardiotoxicity,” said Dr. Compagnone.
“If a drug produces unwanted modulation of mitochondrial dysfunction at a clinically relevant dose it can adversely affect the function of organs such as the liver, the brain, the heart, and the skin, which are sensitive to mitochondrial functioning for energy production.” Using clinically relevant doses also allows comparison of toxicity and efficacy on the same scale leading to a better definition of the safety window, defined by the range of circulating and bioactive doses.