A cruel disease, a glimmer of hope

Author: John Monczunski

Niemann-Pick Type C may be the cruelest disease on the planet afflicting children. The National Institutes of Health refers to the disorder as “childhood Alzheimer’s,” and there’s no doubt the title is deserved.

A degenerative disease that can begin in infancy and end with death in adolescence, NPC slowly cripples the body and mind of its victims. Those afflicted gradually lose all muscle tone, even the muscles that control eye movement. Eventually, children suffering from the disease are unable to swallow. In its terminal stage, Niemann-Pick patients are bedridden and suffer severe dementia.

Estimates are that 1 in 150,000 children are afflicted with the disease. Three of former Notre Dame football coach Ara Parseghian’s grandchildren died from the malady (see “Life in the Abyss” at magazine.nd.edu/news/14936). The Ara Parseghian Medical Research Foundation, established by the family, has partnered with Notre Dame’s Center for Rare and Neglected Diseases to search for a cure.

While no cure now exists, two drugs are being tested. Unfortunately, neither looks encouraging. One drug has limited effectiveness, slowing disease progression but not stopping it. The other has serious side effects.

In March, however, scientists from Notre Dame and Cornell reported a significant breakthrough, offering a glimmer of hope. The team of researchers, led by professors Paul Helquist and Olaf Wiest of Notre Dame and Frederick Maxfield of Cornell, had a hunch that a certain drug already approved to treat T-cell lymphoma, a relatively rare form of cancer, also might affect a protein that regulates cholesterol transport within cells.

That fact is significant since it is known that NPC causes an excessive amount of cholesterol to accumulate in cells. Cholesterol is an essential component of the cell’s membrane and a building block for steroid hormones. However, too much leads to very bad things, namely Niemann-Pick Type C.

When the scientists treated a culture of Niemann-Pick cells with the drug, a histone deacetylase (HDAC) inhibitor, their best hopes were confirmed. Miraculously, the diseased cells reverted to normal.

NPC-damaged cells produce an abnormally small amount of the protein that regulates cholesterol transport, Helquist explains. The HDAC inhibitor drug, however, greatly increases production of that protein, and with a sufficient amount restored, the cell functions normally.

“As encouraging as these results are, this is just a first step,” Wiest cautions. “This compound works in a cell culture. But that is still a long way from an FDA-approved drug treatment. There is a lot of work yet to do, proving the concept in an animal model and other tests before it’s ready for a clinical trial.”

However, since the compound already has been approved as a cancer treatment, much of the preliminary toxicology work, such as assessing side effects, already has been done. Notre Dame researchers are pursuing a strategy of attempting to repurpose FDA-approved drugs to expedite therapies for rare and neglected diseases.

“We understand that many families desperately are seeking help for their children. And, if this compound is effective, we hope that it can be made available as soon as possible,” Wiest says. “But first, we must make sure it is safe and efficacious. We don’t want to make a bad situation worse.”

The Notre Dame chemists have developed and patented efficient processes for producing commercial quantities of the HDAC inhibitor drug and are exploring partnerships with a number of pharmaceutical firms.

Development of drug therapies for NPC is one of several goals of Notre Dame’s Center for Rare and Neglected Diseases. In 2009 Helquist and Wiest began an initiative known as the Drug Discovery Core, through which NPC researchers worldwide may collaborate on the design and synthesis of potential drug treatments. Currently there are collaborations with the medical schools of Cornell, Columbia, Tufts, Washington University and Texas Southwestern, as well as researchers at Purdue and Scripps Research Institute.

John Monczunski is an associate editor of Notre Dame Magazine.