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Stanford University School of Medicine scientists have used bioengineered mice with livers composed largely of human cells to characterize a drug about to enter early-stage clinical development for combating hepatitis C.
Tests using the new mouse model accurately predicted significant aspects of the drug’s behavior in humans — including its interaction with another drug and the profile of its major breakdown products in the body (called metabolites) — far more accurately than would have been achieved using current methods.
All too often, drugs showing tremendous promise in preclinical animal assessments fail in human trials because of unforeseen safety problems, said Peltz. The drug tested in the study, clemizole, was widely prescribed in the 1950s and 1960s as an antihistamine, but it is no longer used because more effective antihistamines now exist, said Jeffrey Glenn, MD, PhD, associate professor of gastroenterology and hepatology, and of microbiology and immunology. Glenn, who is a hepatitis C expert and a co-author of the new study, recently led a team that discovered clemizole impedes replication of HCV. Mary Ann Wijtman The mouse model developed by Gary Peltz's team showed that a drug could be part of a therapeutic approach for the virus that causes hepatitis C. These days, before any drug can go into people it must first be rigorously tested in animals, such as rodents, to determine tolerability or adverse effects and whether it interacts with other drugs patients are likely to be taking. So Peltz and collaborators at the Central Institute for Experimental Animals in Japan built a better mousetrap. The chimeric mice used in the new study varied in the extent to which their livers were composed of human cells. Next, Manhong Wu, PhD, a research associate in the Peltz lab and a study co-author, examined the metabolism of clemizole in both humans and several ordinary mouse strains. However, postdoctoral scholar Yajing Hu, PhD, who shares first authorship with visiting professor Toshiko Nishimura, MD, PhD, found that the chimeric mice did produce M1, roughly in proportion to the extent to which their own liver cells had been replaced by human ones. Then Peltz and his colleagues tested the chimeric mice’s capacity to predict potential interactions between clemizole and other drugs. To see if this held true in humans, Peltz’s group initiated a small pilot study with three HCV-positive individuals. All of the findings validate the utility of the new mouse model as well as clemizole’s clinical potential, said Peltz. Bruce Goldman is a science writer for the medical school’s Office of Communication & Public Affairs.
Stanford Medicine integrates research, medical education and health care at its three institutions - Stanford University School of Medicine, Stanford Health Care (formerly Stanford Hospital & Clinics), and Lucile Packard Children's Hospital Stanford. A well-known Eastern medicine supplement may help avoid the most common cause of liver transplantation, according to a study by researchers at the School of Medicine.
Stanford University School of Medicine scientists have discovered a novel class of compounds that, in experiments in vitro, inhibit replication of the virus responsible for hepatitis C. Stanford Medicine's unrivaled atmosphere of breakthrough thinking and interdisciplinary collaboration has fueled a long history of achievements.
When treatment guidelines for a particular disease emerge, they are often published in a peer-reviewed medical journal, which can take up to three years.

Anyone can submit a comment any time after publication, but only those submitted within 4 weeks of an article’s publication will be considered for print publication.
Slideshare uses cookies to improve functionality and performance, and to provide you with relevant advertising. SBEL1 is a compound isolated from Chinese herbal medicines that was found to inhibit HCV activity by approximately 90%. A drug may prolong or attenuate another medication’s activity by, for example, affecting how the second drug is metabolized.
More than 150 million people are infected with HCV, the leading cause of liver transplant operations in the United States and primary cause of liver cancer. But because it was approved before the advent of some testing requirements now routinely in place for new drugs, little is known about how the compound is metabolized or how it interacts with other drugs in the human body, Glenn said.
But mice metabolize things differently from humans, largely because our livers are different. It operates like a set of carefully placed workstations in an assembly line, in which batteries of enzymes (protein machines that do most of the body’s work) manufacture substances vital to our survival as well as metabolize ingested substances, including drugs. So the two species will produce different metabolites or different amounts of the same metabolites from the same drug. In 2011, they produced a genetically engineered mouse in which the liver could be humanized without inducing ongoing liver toxicity.
Their overall metabolic profiles could be likened to two images projected in juxtaposition on a screen, with the difference between the two images corresponding to the extent that a mouse’s liver had been humanized.
Clemizole’s metabolic pattern was the same in all of the tested strains, but was quite different from that observed in the blood of 10 human subjects. Further studies showed that M1 itself has antiviral activity that can contribute to clemizole’s overall potency in humans — a fact that would have been ignored on the basis of testing clemizole in ordinary mice.
They picked a drug called ritonavir, which is known to interfere with a metabolic enzyme that is crucial to the breakdown of many drugs in humans. As occurred in the chimeric mice, co-administration of ritonavir caused a substantial increase in the blood levels of clemizole in two subjects and a smaller increase in the third subject. Clemizole has a half-life of only about 15 minutes in mice, so on the basis of ordinary mouse studies it might well have been discarded, he said. One University of Alabama at Birmingham infectious diseases expert recently helped develop new Hepatitis C virus (HCV) guidelines that can be updated and published as new data emerge and new therapies are approved. One month after publication, editors review all posted comments and select some for publication in the Letters section of the print version of Annals. Its findings hold potentially huge implications for drug development in general, because key aspects of the tested drug’s activity and properties would likely have gone unnoticed using the kind of mouse study that is the current standard for preclinical tests of candidate drugs. With more than 30 percent of all people over age 57 taking five or more prescription drugs at any given time, that’s no trivial matter.

Attempts to get around this have included bioengineering so-called chimeric mice that have “humanized” livers, in which mouse liver tissue has been at least partly replaced by human cells. The researchers administered a short-acting, non-toxic dose of a drug to mice that had been bioengineered so that the drug would activate a cell-killing mechanism only within their liver cells. To determine the extent of liver humanization for each mouse, Peltz and his associates measured blood levels of the human version of albumin, a circulating protein produced in the liver.
More than half of the total amount of clemizole plus its metabolites in human blood consisted of a single metabolite, known as M1. Chimeric mice were first treated with clemizole alone, and later given a combination of clemizole and ritonavir.
HCV — which affects more than 3 million people in the United States and is the leading cause of cirrhosis and liver cancer, according to the Centers for Disease Control and Prevention — last saw guidelines released in 2011. An unauthorized jargon has evolved to accommodate these subtypes, and it may wrongly or prematurely connote their validity.
Importantly, the results strongly hint that the drug, clemizole, could be both safe and an effective drug-cocktail component in humans infected with HCV, the virus that causes hepatitis C. These efforts have involved introducing toxins or genetic defects to kill off the intrinsic mouse liver cells to make room for their replacement by human ones.
Once this drug was cleared, the implanted human liver cells could develop normally in their new environment, contributing to a reconstituted liver that largely recapitulated the architecture and chemistry of a functioning human liver. A mathematical algorithm the researchers developed allowed them to accurately determine which metabolites, and how much of each, could be attributed to mouse and human liver cells, respectively. Afterward, the scientists measured levels of clemizole and its metabolites in the mice’s blood. Patients with cryptogenic disease, mixed viral and immunologic features, and atypical findings lack a formal designation. But the organ’s ongoing malfunction impaired human-cell growth or made “readouts” from drug testing suspect. The human cells produced human metabolites; the mouse cells continued to produce mouse metabolites. Co-administering ritonavir caused clemizole’s blood level to increase and to remain elevated for longer than was the case with clemizole alone.

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