The researchers said evidence from their lab and others backs up the claim.

A class of drugs known as farnesyl transferase inhibitors, or FTIs, can fix an abnormality in laboratory-grown cells engineered to mimic cells from the patients, the researchers explained.

Such cells have nuclei that aren’t round like normal nuclei. They instead have multiple “lobes” and can even look like a cluster of grapes or bubbles. 

Treating these engineered cells with an FTI currently in clinical trials in cancer patients restored the cells to normal appearance, the researchers said. They cautioned, however, that no one knows whether making the nuclei look normal would actually lead to a cure. 

The researchers reported their findings Sept. 26 in the advance online edition of the research journal Proceedings of the National Academy of Sciences.

The discovery could be particularly fortunate, the researchers said, because drug companies typically don't put much effort into curing rare conditions such as this one. It affects about one in 8 million children, the researchers said.

A genetic mutation makes the cells of progeria victims produce a faulty version of a molecule called lamin A. This molecule, a protein, is a component of the membrane that covers the nucleus of cells. Exactly how this leads to their condition is unclear.

But the drug seems to work, the researchers said, by blocking a processing step that the faulty molecule undergoes just after it is produced.

It’s “really exciting to have leapfrogged from studying a fundamental process to finding evidence that an existing drug might be useful in treating a devastating disease in children,” said Susan Michaelis, Ph.D., professor of cell biology at the school.  

Cells continually produce a wide variety of molecules, mostly called proteins. These both serve as building blocks of the cells themselves and conduct the activities needed to keep the cells alive.

After a protein is first produced, it usually undergoes some additional processing by cellular machinery to shape it into its final form. In progeria patients, it seems something goes wrong with this processing for lamin A. 

Normal processing of lamin A, Michaelis said, involves at least two steps. First, a couple of small modifications are made to one end of the molecule. Second, that same end is chopped off and thrown away. 

Thus, it might seem the first step is pointless. 

In fact, it does seem to be useless in mammals, the researchers said. It may occur, they added, because it’s an evolutionary holdover from much simpler organisms, such as yeast, where it does have a purpose. The yeast actually uses the chopped-off end.

In progeria victims, though, the first step is apparently worse than useless. This is because the second step, the removal, fails to occur. So the alterations made in the first step stay. This was discovered in 2003, Michaelis said.

After the discovery, she said, she conjectured that progeria might somehow be a result of these modifications staying in place. 

She and Monica Mallampalli, a postdoctoral fellow at the school, set out to test the idea. Mallampalli genetically engineered human cells to have either of two mutations in the gene that has the code for producing lamin A.

One mutation halted the processing at the very beginning, by preventing the main alteration. The other affected the end of the process, by preventing removal of the modified bit.

“Neither has the correct lamin A protein, but only one has a modified protein hanging around,” said Michaelis. But only the modified protein had the problems seen in cells with the progeria syndrome mutation, she added. 

The modification involves the addition of a fatty appendage called farnesyl to the end of the protein.

Mallampalli also experimented with the version of mutant gene that causes the syndrome in actual patients, called progerin. She modified it to again prevent the addition of farnesyl. Sure enough, even though the cells still didn’t have normal lamin A, their nuclei looked normal, the researchers said.

Finally, the researchers studied whether they could get the same improvements in a simpler way. They decided to try a drug that would disrupt the action of another molecule altogether: the enzyme that adds the farnesyl to the lamin A protein. 

This enzyme is called a farnesyl transferase, since it transfers farnesyl. And farnesyl transferase inhibitors are so named because they block the enzyme. It’s believed that they do this by sticking to a protein in the same place where the enzyme would add the farnesyl, snarling the process.

Michaelis obtained an FTI compound and tried it. 

“We were thrilled,” said Michaelis. “The experimental drug did the trick.” FTIs are already in advanced clinical trials with cancer patients and seem quite safe, she added, so hopefully they can be tested in progeria patients soon.

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