NGF Blog


Developing Enzyme Replacement Therapy – An Insider’s Perspective

Enzyme replacement therapy (ERT) was first approved for use by the U.S. Food and Drug Administration in 1991. This revolutionary therapy was the first discovered to correct the underlying enzyme deficiency that causes the non-neuronopathic symptoms of Gaucher disease types 1 and 3. Today, thousands of people living with Gaucher disease receive ERT infusions about every two weeks.

ERT wouldn’t exist if it wasn’t for a group of researchers who devoted a large part of their careers to studying lysosomal storage diseases like Gaucher disease. Dr. Clifford Steer, Professor of Medicine, Division of Gastroenterology, Hepatology, and Nutrition at the University of Minnesota, was instrumental in determining how to make ERT effective within the human body. He shares his experiences as a researcher who helped bring ERT into reality.

Drug Metabolism and Liver Cells

To understand Dr. Steer’s contribution to the development of ERT, it’s important to understand how the human body processes medications. The liver metabolizes most drugs, including prescription medications, over-the-counter drugs, and supplements. Drug metabolism refers to the processes by which the body chemically alters a medication.

In most cases, changing the chemical composition of a medication produces its therapeutic effects. Specialized liver cells known as hepatocytes are primarily responsible for the uptake of any drug entering the body. Other liver cells, such as liver sinusoidal endothelial cells and Kupffer cells, help hepatocytes metabolize drugs to a lesser extent.

Enzyme replacement, a novel concept

All people living with Gaucher disease lack sufficient amounts of the enzyme glucocerebrosidase (GCase). This enzyme is essential for breaking down the fatty molecule glucocerebroside. When GCase levels are too low, glucocerebroside builds up within cells throughout the body. This changes cellular functions and causes the symptoms of Gaucher disease.

As a first step toward enzyme replacement therapy, researchers geared efforts toward collecting large quantities of purified GCase. Only with large quantities of purified GCase could scientists explore its therapeutic benefits in Gaucher disease patients. Researchers developed methods by which they could purify GCase on a large scale, making the enzyme readily available for other research efforts.

GCase, liver metabolism, and initial setbacks

Initially, two individuals—a 15-year-old boy and a 51-year-old woman—received GCase intravenously (IV) to test the enzyme’s effectiveness. These early Gaucher disease patients experienced a 26% reduction in glucocerebroside within liver cell tissue samples.

The following year, another patient received an IV infusion of GCase but only experienced an 8% reduction in glucocerebroside. Also, some animal studies showed IV infusion did not effectively deliver GCase to some liver cells, especially Kupffer cells. These inconsistent clinical results prompted further study, but no one method produced significant positive effects for any patient undergoing treatment.

Early Research at the NIH

In 1976, Dr. Steer began working at the National Institutes of Health (NIH) as a gastroenterologist with a special interest in liver diseases. “I noticed that no one at the NIH knew how to isolate (collect) liver cells from animal models for use in clinical studies. I decided to design a method for doing so. I’m happy to say I was the first person to actually isolate hepatocytes while working at the NIH,” says Dr. Steer.

“Then, I started doing a lot of research on isolating liver cells from rats. Over the course of time, I became interested in carbohydrate receptors on certain types of liver cells. Gilbert Ashwell, who is still world-renowned for his work on carbohydrate receptors on hepatocytes, was my role model and teacher. I became very knowledgeable about carbohydrate receptors on different types of liver cells.”

Researchers had already determined GCase expressed several types of carbohydrates as binding receptors on its surface. In other words, carbohydrate compounds were present on the surface of GCase. Other types of cellular molecules, such as enzymes, would bind to these carbohydrates, triggering certain chemical responses. But GCase still wasn’t effective in the treatment of Gaucher disease for many people. Investigators had to figure out how to make more liver cells accept GCase by binding to its carbohydrate receptors.

Carbohydrate Binding With GCase

Dr. Steer collaborated with Dr. John Barranger and Dr. F. Scott Furbish to figure out how to get GCase into more liver cells. Dr. Steer notes, “At the end of the day, we had two groups working together. One group worked on glucocerebrosidase and enzyme replacement therapy. I focused on detailing, characterizing, and even targeting specific cellular receptors within the liver. That’s how this all developed.”

“At first, we looked at some of the carbohydrate receptors on certain types of liver cells. We wanted to deliver GCase to Kupffer cells, so I focused on those carbohydrate receptors first. At the same time, the other group took GCase and started chiseling it down. Eventually, they got GCase to have a carbohydrate moiety, or functional group, which was exposed. This moiety would bind to the carbohydrate receptors on Kupffer cells,” Dr. Steer explains.

But the issue of cell purity affects almost all clinical studies involving cellular materials. “If we didn’t have a pure, noncontaminated population of Kupffer cells, we wouldn’t have known what was giving rise to what. If we’d had contaminated cells that made up even just 10% of the entire lot, we would have had major problems,” says Dr. Steer.

To avoid this potential issue, Dr. Steer worked on new techniques to ensure cell purity. He successfully created ultra-pure populations of different types of liver cells, including Kupffer cells. These pure cellular samples helped researchers determine how to target GCase to Kupffer cells.

Enzyme Replacement Therapy Begins

“Once we made our discovery, we published a handful of seminal papers that helped direct the development of commercially-available glucocerebrosidase for Gaucher disease treatment.”

Dr. Roscoe Brady and many others at the NIH conducted exhaustive clinical trials to evaluate the modified GCase’s safety and efficacy. “Glucocerebrosidase is now considered standard care for people with Gaucher disease,” says Dr. Steer.

The Future of Clinical Research and Gaucher Disease

ERT continues to provide therapeutic benefits for thousands living with Gaucher disease. But researchers continue to explore ways to better manage symptoms—or cure the disease completely. “Gene therapy is really a hot button issue today. When you look at the development of technologies over the course of time, the 90s saw a robust effort to understand and implement effective gene therapy. Since then, gene therapy has really been under the microscope,” says Dr. Steer.

“Eventually, microRNAs became popular, then gene editing. Then, stem cells took over everything. More of these advanced technologies are going to be developed over the course of time,” says Dr. Steer.


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