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A promising treatment for incurable kidney disease

01/01/2011

Andrew G. Plaut, MD, and Jiazhou Qiu, MD, of Tufts Medical Center have developed techniques to use IgA protease to clear IgA1 protein from kidneys. In other words, these two clinicians are on their way to developing a treatment for one of the leading causes of kidney failure worldwide: IgA nephropathy (IgAN).

As diseases go, IgAN has a low profile among Americans. A disorder that can lead to total kidney failure, it is present in the United States, but it is much more prevalent in Asia. Often, it is not recognized until it is far along.

“Several factors make this illness fly under the radar in the Western world,” says Dr. Plaut. “It’s not common in the West, it has a very slow progression and it requires a kidney biopsy for diagnosis — a procedure many clinicians are reluctant to order because effective treatment is not available.

“The illness is common in Japan, which screens children for IgAN rigorously. It’s estimated that more than 1 percent of the population in China is afflicted with it. Singapore and South Korea have similar numbers, and it’s probably abundant in India. It’s a serious problem but there really are no effective treatments and no cures.”

That, hopefully, will change as a result of work done by Drs. Plaut and Qiu at Tufts Medical Center, where they’ve pioneered techniques of using proteases — enzymes whose many functions include roles in immunity.

IgAN develops when immunoglobulin A (IgA1) proteins in the blood accumulate in an affected kidney’s million glomeruli — the tiny capillaries that filter wastes from the bloodstream. As these deposits build up over time, the glomeruli become inflamed and damaged, slowly losing function and eventually closing down altogether. Treatment has generally been focused on drugs that limit inflammation, but, at best, they only slow the loss of kidney function.

IgA is one of five major types of antibodies that play important roles in fighting off pathogens. IgA1, present in the blood of all healthy persons, is the version of IgA that causes IgAN. Working with bacteria in the 1970s, Plaut realized that an IgA protease produced by a bacterium could be used to clear IgA1 proteins from affected kidneys.

“We studied the unique IgA proteases for a long time,” Plaut notes. “In the 1980s we began to gain insight as to how these enzymes could be used to cut the human IgA1 molecule. It’s effective for bacteria because it cuts IgA antibody in half, making it useless. And the only thing that it cuts is IgA1. This makes it very useful for our treatment plan.”

Working with a Case Western Reserve University team headed by Michael E. Lamm, MD, and Steven Emancipator, MD, Plaut and Qiu conducted animal tests in 2004. They demonstrated that the protease efficiently removed some 85 percent of human IgA1 they had deposited into the kidneys of mice.

According to Nina Green, director of the Office for Technology Licensing and Industry Collaboration at Tufts Medical Center, Drs. Plaut and Qiu disclosed their invention to Tufts Medical Center in 2003. Patented by the Medical Center that year, development of the technology is currently in the preclinical stage by IGAN Biosciences Inc., a Boston-based company founded by Drs. Plaut and Qiu, and by BioMarin Pharmaceutical Inc. in Novato, CA.

“Preclinical work is something BioMarin is good at,” Qiu says. “They’re doing the animal testing, developing techniques for producing the protease in large amounts, everything needed to take the product to the Food and Drug Administration to apply for clinical trials.” It’s a three-party agreement between Tufts Medical Center, IGAN and BioMarin.

Plaut describes the magnitude of this new technology, should clinical trials be successfully navigated: “As many as 40 percent of IgAN patients go on to experience complete kidney failure and the need for renal dialysis or a kidney transplant. This is a disease that severely impacts people’s lives. It can kill them. We have a chance to eliminate it.”