Researchers Study Ebola Link to Gene in Rare Disease

November 3, 2014

In the search for answers about Ebola, researchers are starting to look at an unexpected group of people: parents with children who have the fatal genetic disease Niemann-Pick Type C.

The intersection between research in Ebola and NPC disease was surprising, and came after two scientific papers were published in 2011 demonstrating that a protein made by the same gene related to NPC disease is essential for Ebola infection.

Ebola uses the so-called NPC1 protein made by the gene to get into the cell and replicate the virus.

Now, research suggests that the gene that causes NPC disease may also offer protection against Ebola.

A group of researchers at Albert Einstein College of Medicine in Bronx, N.Y.; the U.S. Army Medical Research Institute of Infectious Diseases in Frederick, Md.; Netherlands Cancer Institute and Harvard Medical School, studied mice that have only one normal copy of the NPC gene—comparable in a way to carriers of NPC disease—and found that although they get infected with Ebola, a large proportion of them survive the disease.

Mice with two working copies of the gene— comparable to the general population—that got infected with Ebola all died.

Mice that don’t have any normal copy of the NPC1 gene all survived Ebola infection. People whose cells lack or don’t have properly functioning, or defective NPC1 protein, get NPC disease.

There are several research groups looking for compounds that can block the protein on the Ebola virus from coming into contact with NPC1 protein.

These drugs ultimately could be used as a means to prevent people from getting infected or for making an infection less severe.

Parents of children with NPC disease are supporting research into the Ebola-NPC connection. Brian Chan of Los Angeles, who has a child with NPC disease, is funding a project to study cells from people who are known to be carriers for NPC disease as well as those from survivors of previous Ebola outbreaks. Researchers want to know if Ebola survivors also have mutations on one copy of their NPC gene. And by studying cells from parents who are NPC carriers, they hope to better understand how changes on the NPC gene might lower the risk of dying from Ebola virus.

“We want more research on the NPC gene,” said Chris Hempel, a Reno, Nev., mother of two children with NPC disease who is helping organize a collection of blood and tissue samples from parents. There are an estimated 500 cases of NPC disease diagnosed world-wide, mostly children.

Researchers in the Ebola field say there is still a lot to learn. In mice, at least, they believe that the NPC1 gene plays an essential role in Ebola infection, but how that finding translates into humans is still under study. They also contend that there are a number of different genes and other factors, from the amount of virus to someone’s underlying health, that likely play a role in Ebola survival as well.

John Dye, principal investigator of the NPC-Ebola research at the U.S. Army research institute, said that he hopes Ebola research can help prevent future epidemics like the one in West Africa, where nearly 5,000 people have died. But he also hopes it will yield information that also benefits patients with NPC disease and their parents.

Scientists don’t know a lot about how many people in the general population may be carriers for NPC disease. Coriell Institute for Medical Research has 47 NPC1 cell lines, but almost all of them are from patients with NPC disease. Ms. Hempel and Mr. Chan are working to get other parents of NPC children to donate cells so that patients and carriers can be more easily studied.

There are also efforts by parents and scientists to get genetic information collected by companies that have sequenced the NPC1 gene to publicly share information about different mutations.

Kartik Chandran, the principal investigator on the NPC-Ebola research at Albert Einstein College of Medicine, said researchers don’t know yet why the mice who were NPC carriers had a survival advantage over normal mice.

It may be that lower levels of NPC1 protein reduce the amount of infection in some cells.

Or that lower NPC1 levels has some other effect on the ability of the mice to fight infection.

Steven Walkley, an Albert Einstein scientist who studies NPC disease and is a collaborator on the Ebola-NPC studies, said that the idea that “carriers” for certain genetic diseases may enjoy some sort of of protection from another disease is well known in genetics. For example, carriers for the blood disorders sickle-cell disease and beta thalassemia may be protected against malaria.

Studying NPC disease is what led to the discovery of the NPC1 gene and the importance of the NPC1 protein. “This shows the value of the study of rare disease,” Dr. Walkley said.
Amy Dockser Marcus of the Wall Street Journal

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