We know that the liver and the kidneys play crucial roles in drug metabolism and excretion. Recently announced collaborative efforts harness powerful current technologies to explore promising new treatments that mitigate damaging effects on the liver and kidneys. Better R&D on drug-induced kidney damage and better modeling of liver disease are the focus of separate efforts on the part of researchers assisted by Agilent Technologies and a collaboration between Organovo and Viscient Biosciences, respectively.
It is well established that some drug therapies can cause toxic effects to kidneys. While lab tests can easily find that damage, what’s missing is a way to identify the patients most likely to experience the organ damage before it happens. In 2015, Dr. Lawrence Lesko, clinical professor and director of the Center for Pharmacometrics and Systems Pharmacology at the University of Florida, received an Agilent Technologies Thought Leader Award in support of his research into preclinical toxicological assessments of new medicines.
Using a unique combination of liquid chromatography, mass spectrometry systems and software analytics, Lesko provided a useful picture about how certain drugs become toxic, and potential methods to mitigate drug-induced kidney damage without the need to discontinue treatment. He noted that lab test indicators for impaired renal function are changes in serum creatinine, blood urea nitrogen and creatinine clearance. “The problem,” he says, “is the changes in these biomarkers occur after the drug substantially damages the kidney, where you can’t necessarily reverse it and the patient has to endure long-range suffering.”
He invested the award resources into a search for biomarkers that could better predict the side effects of new medicines. Using Agilent instruments (a combination of highly accurate liquid chromatography and mass spectrometry systems) to gather mountains of data, he then used Agilent software (MassHunter, Mass Profiler Professional and Pathway Architect) to analyze it. He was able to develop a metabolomic profile that could provide early warning that a drug is harming the kidneys.
In one early breakthrough, he and his colleagues discovered the transport mechanism used by a chemotherapy called cisplatin to get into the kidneys, then showed that blocking the pathway with a second drug, cimetidine, reduced cisplatin levels in a critical part of the kidneys. “We know that cisplatin, a chemotherapy drug widely used in oncology, gets into the kidneys through a transport mechanism called OCT 2 (short for organic cation transporter 2), which takes it from the blood into the renal cortex,” Lesko explains. “What if we gave an antidote that blocks OCT2 transport before the cisplatin? [We] reduce the toxicity of a drug by giving a second drug a priori that minimizes the toxicity mechanistically—in this case, by blocking the OCT 2 pathway.”
The ability to proactively identify biomarkers and introduce a mitigating agent can have long-term positive benefits on drug discovery and development. Renal toxicity has been a primary reason pharmaceutical companies have suspended drug development projects, and why doctors discontinue certain chemotherapy and antimicrobial treatments. To offer the treatment to eliminate the toxicity may allow for a new class of medicines to be used in critical clinical settings.
Meanwhile, Organovo and Viscient Biosciences recently announced their collaboration to develop a custom research platform for studying liver disease. Organovo is known for its functional, 3D tissue models that remain viable to allow for preclinical testing and drug discovery research. Viscient also uses 3D culture technology to develop drugs in a variety of therapeutic areas. Working together, Viscient can continue its early discovery work for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) able to be tested on superior tissue models.
“We continue to have excellent traction with a wide range of biopharmaceutical companies in evaluating our tissue systems to facilitate the discovery and development of novel drug candidates to treat liver disease,” said Taylor J. Crouch, CEO of Organovo. “Our 3D disease models have the unique capability to demonstrate drug mechanisms of action and efficacy in a setting that closely mimics human livers. We’re proud to collaborate with Viscient’s talented team, as they have a strong understanding of our expertise. Our aim is to establish a custom platform that will support high-value drug profiling and ultimately move our collaboration into a steady-state relationship.”
“Viscient is a strong believer in unlocking the power of 3D bioprinting to bring cures and treatments to patients with few options today,” commented Keith Murphy, CEO, Viscient Biosciences. “In our pursuit of breakthrough therapies in important areas of medicine, we’re eager to tap into novel, complex and more accurate disease models. Organovo’s technology provides the potential for valuable and unprecedented insights as we target new drugs in areas of unmet medical need and strong commercial potential.”
Deteriorating liver function is a growing and serious public health concern, with an estimated 100 million adults in the U.S. afflicted with NAFLD, while up to 20 million more Americans are projected to have NASH. Left unchecked, these diseases can progress to cirrhosis and cancer, with NASH being the second leading cause of liver transplants in the United States. Despite decades of intense research worldwide, the understanding of NAFLD progression and the development of novel therapeutic approaches have been limited by the lack of advanced systems that mimic human liver biology over an extended period of time.