The Use of Stem Cells in Drug Development

Why is it that one person can have surgery and wake up, eat a full lunch and show no ill effects while others are sick for several days after receiving general anesthesia?

The fact is that we all process drugs differently, and these differences are a function of the genetic diversity between all of us. These differences stem from 1) different targets; 2) different liver enzyme activities; and 3) different levels of absorption, excretion and distribution.

A few examples might be illustrative. It is fairly well established that a particular type of blood pressure medicines called “ACE inhibitors” do not work terribly well in African-Americans (see Park IU, Taylor AL. Ann Fam Med. 2007 Sep-Oct;5(5):444-52). The reason for this is that the target of ACE inhibitors, the enzyme angiotensin converting enzyme, which is mercifully abbreviated ACE, works on a substrate that already exists at low concentrations in most African-American patients. Thus a target difference causes differential responses to particular blood pressure medicines.

As a second example, two liver enzymes that degrade drugs, Cyp2C19 and Cyp2D6 are encoded by genes that are subject to genetic variation. In 3-10% of whites, the Cyp2D6 enzyme does not completely function and the drugs processed by this enzyme, a blood pressure medicine called debrisoquine and a heart medicine called sparteine, show impaired degradation. Thus these patients are in danger of overdosing on these drugs at normal dosages, since they are degraded and excreted at such low rates. Other people, however, have a version of Cyp2D6 that is hyperactive. This variant is most commonly found in Ethiopians and Saudi Arabians that consequently, drugs degraded by this enzyme, such as tricyclic antidepressants (e.g., nortriptyline) must be dosed at two the three times the normal concentration. Also, some drugs are given as prodrugs, which are inactive until the liver activates them. In individuals with the overactive Cyp2D6 enzyme variant, a prodrug, such as codeine is overactivated and at normal doses, causes severe side effects (stomach pains). Thus a distinct enzyme difference causes different clinical outcomes with the same drugs (see JK Hicks, et al., Clin Pharmacol Ther. 2013 May;93(5):402-8).

So then, how do we test for drug safety and efficacy given these variations in drug metabolism?

Stem cell technology has the ability to improve drug testing in a multitude of ways. Drug safety can be tested with stem cells as can drug efficacy without feeding them to human volunteers.

Now scientists from the University of Edinburgh have shown that stem cell-based drug tests are almost ready for the prime time. David Hay from the Medical Research Centre for Regenerative Medicine at the University at the University of Edinburgh and his colleagues have generated cell in the laboratory that reach the gold standard required by the pharmaceutical industry to test drug safety.

In this study, the Hay laboratory made liver cells from H9 human embryonic stem cells and from 33D6 human induced pluripotent stem cells. Since is the liver is the main organ that biochemically processes drugs in our bodies (a phenomenon known as biotransformation), testing drug safety in cultured liver cells makes good sense.

Next, Hay and his colleagues found that these pluripotent-derived liver cells were equally effective in drug safety tests as frozen human liver tissue extracted from cadavers. Such livers are in short supply and the results researchers derive from them varies wildly according to the genetic make-up of the donor. Thus frozen liver tissue is not optimal for such drug testing protocols.

However, these drug-testing protocols that use stem cell-based protocols can provide reproducible drug safety results and can also be adapted for individuals with particular genetic compositions who process drugs differently from other people.

David Hay explained it this way: “Differing genetic information plays a key role in how patients’ livers process drugs. We are now able to efficiently produce human liver cells in the laboratory from different people model the functional differences in human genetics.”

Hay and others hope to generate liver cells that contain distinct DNA sequences that will reflect the genetic variations in metabolism found in the population. These cultured liver cells from human pluripotent stem cells can be used to identify differences in drug biotransformation.

These laboratory-generation liver cells could also be used to screen certain drugs that need close monitoring in order to optimize the efficacy of patient treatment, and the safety of these treatment regimes.

Hay and his colleagues are working with Edinburgh BioQuarter in order to form a spin-off company that will commercialize this research and its clinical ramifications.

Umbilical Mesenchymal Stem Cells Improve the Symptoms of Patients With Decompensated Liver Cirrhosis

One of the most central organs for the body’s metabolism is the liver. When the gastrointestinal tract absorbs food molecules, the first stop for most of these molecules is the liver. The liver makes many blood-specific proteins, detoxifies foreign molecules to make them more water-soluble so that the body can excrete them, and stores energy reserves in the form of glycogen. Consequently, damage to the liver from chronic liver infections (e.g., hepatitis B & C, bilharzia or schistosomiasis, illegal drug use, etc.), alcoholism, or exposure to liver-damaging chemicals (carbon tetrachloride, chloroform, etc.) seriously compromises the capacity of the body to store energy, process food molecules, make blood specific proteins (which include clotting factors), and process and synthesize metabolic wastes. Repeated damage to the liver causes extensive scarring and deposition of fatty tissues, and such a condition is called “cirrhosis.”

Cirrhosis ultimately leads to liver failure, and tough scar tissue with nodules replaces once healthy liver tissue. There are two main types of cirrhosis. Compensated cirrhosis of the liver refers to early liver damage in which the body functions well despite the damaged liver tissue. Even though liver function is decreases, the body still operates within normal parameters, and the patient often shows no symptoms of disease. Even though people with compensated liver cirrhosis are often asymptomatic, they may display symptoms of weakness, fatigue, loss of appetite, vomiting, weight loss and easy bruising. Liver function tests may reveal increased levels of certain liver enzymes. Liver damage is not reversible, but treating the underlying cause can prevent further damage. Additionally, constant monitoring is required for the early detection of loss of liver function that leads to life-threatening complications.

Decompensated liver cirrhosis is a life-threatening complication of chronic liver disease, and it is also one of the major indications for liver transplantation. The symptoms of decompensated cirrhosis are internal bleeding from the esophagus (bleeding varices), fluid in the belly (ascites), confusion (encephalopathy), yellowing of the eyes and skin (jaundice). When someone becomes this sick, there is little to be done, but receive a liver transplant.

Can stem cells help patients with decompensated liver cirrhosis? Perhaps they can. A paper from the Journal of Gastroenterology and Hepatology (2012; 27 Suppl 2:112-20) has examined the ability of human umbilical cord mesenchymal stem cells to improve symptoms in patients with decompensated liver cirrhosis (DLC). The paper’s first author is Z. Zhang and the title of the paper is “Human Umbilical Cord Mesenchymal Stem Cells Improve Liver Function and Ascites in Decompensated Liver Cirrhosis Patients.” These authors are from the Research Center for Biological Therapy at the Beijing 302 Hospital, in Beijing, China.

In this study, the safety and efficacy of umbilical cord-derived MSCs (UC-MSC) were infused into in patients with DCL. They used a total of 45 chronic hepatitis B patients, all of whom were diagnosed with DCL. 30 patients received transfusions of UC-MSCs, and another 15 patients were given saline as the control. After transfusions, all 45 patients were followed for a 1-year follow-up period.

In none of the 45 patients who were infused, were any significant side-effects observed. Also, there were no significant complications were observed in either group. As to the symptoms suffered by the patients, those who had received the UC-MSC transfusion showed a significant reduction in the volume of ascites in comparison to those patients who had received the control saline transfusions. When liver function parameters were examined, UC-MSC therapy also significantly increased of serum albumin levels (albumin is made by the liver), decreased in total serum bilirubin levels (bilirubin is a waste that is processed by the liver), and stabilized the sodium levels for patients (patients with cirrhosis have low blood sodium levels).

Further follow-up of these patients is clearly warranted, but for the year follow-up. It seems clear that UC-MSC transfusions are clinically safe. Furthermore, when compared to controls, they also seem to improve liver function and reduce the volume of belly fluid in patients with DCL. UC-MSC transfusions might represent a novel therapeutic approach for patients with DCL.