First Treatment Found For Rapid-Aging Disease In Children

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Researchers have found the first treatment for progeria, a rare "rapid aging" disease in children. (Courtesy of the Progeria Research Foundation)
Researchers have found the first treatment for progeria, a rare "rapid aging" disease in children. (Courtesy of the Progeria Research Foundation)

I first heard of progeria in "When Bad Things Happen To Good People," by Harold Kushner. The author, a Natick rabbi, lost his 14-year-old son to the disease, a rare genetic defect that causes accelerated aging and effectively turns children into little old people, afflicted by strokes and heart attacks. They die young, of old age.

So my first reaction to today's big news about the first promising treatment for progeria was: "Now at least the bad things that happen to some good people may not be quite so bad."

A paper just published in the Proceedings of The National Academy of Sciences reports on a clinical trial for the first known treatment for progeria, and the findings are highly promising. The drug used, Lonafarnib, originally aimed at fighting cancer, appeared to help with weight, bone structure, and most importantly, artery health in 28 children with progeria.

That the drug appeared not only to slow but to reverse some aspects of damage to the children's blood vessels "is a tremendous breakthrough, because cardiovascular disease is the ultimate cause of death in children with progeria,” said Dr. Leslie Gordon in the press release. She is the lead author of the study, medical director for the Progeria Research Foundation, and the mother of a child with progeria. (She's also affiliated with Boston Children's Hospital, Harvard, Brown and Hasbro Children's Hospital.)

I challenged her on "breakthrough" — I tend to be so cautious with that word that I'm downright allergic to it. Her justification:

[module align="right" width="half" type="pull-quote"]"This is a 100% fatal pediatric disease and we had no idea whether it could be influenced in any way by any drug treatment.'[/module]

"I do think it can be called a breakthrough, and the reason is that prior to this study finding, we had no idea whether we could offer anything for progeria at all. This is a 100% fatal pediatric disease and we had no idea whether it could be influenced in any way by any drug treatment.

So to me, the breakthrough here is that we have findings that show that progeria can be altered. Not only in the rate of weight gain but that the vasculature can be influenced and the bone can be influenced. That's a real breakthrough that gives us tremendous hope that by finding more treatments and more ways to get at the disease process in progeria — with the protein called progerin — that we can actually have an impact on the disease."

The clinical trial was only 2-1/2 years long, she noted, so it is not yet known whether the drug's benefits will translate into longer lives. But "the breakthrough element is really, 'Oh my gosh, for the first time, we know the disease can be influenced.'"

I also spoke today with Dr. Mark Kieran, senior author of the progeria study and director of pediatric medical neuro-oncology at Boston Children’s Hospital and Dana Farber Cancer Institute. Our conversation, lightly edited:

So it sounds like this is one of those times when science works just as it’s supposed to: Researchers found the gene, figured out what it did, and then corrected it, at least partially??

Dr. Kieran: Ten years ago, people didn’t even know that this was really a genetic disease. There's a fascinating story there: When Francis Collins, now head of the NIH, discovered the mutation, it turned out the defect was not actually in the gene. The area where the mutation is acts as a kind of recognition site for a pair of scissors that come along later and break the molecule in two, and because that little dotted line is missing, there's no cut.

So not only was it remarkable that in a 10-year period they figured it out, and it turned out not to be what people thought it would be — in a gene that no one thought would in any way, shape, or form be related to aging — but when discovered, the defect was in the inability of this molecule to remove something that attaches at another stage.

(Courtesy of the Progeria Research Foundation)
(Courtesy of the Progeria Research Foundation)

That kind of really opened up the research. He was now able to make mice that had the same defect. Every researcher interested in this area was suddenly able to do the same thing, and because we knew the defect was in what we call a splice site — a place where you break the molecule into two — there was no way to correct this splice site but there happened to be a drug in clinical trials that prevents the thing that can’t be spliced out from getting put on in the first place.

So the real issue here, the concept of what became the idea for therapy, was not a cure for progeria; to cure the disease you’d have to go in and correct all the mutated genes and we can’t do that yet. But plan B was: Okay, much like insulin is not a cure for diabetes but it is an effective treatment, the question was, if you could go in and stop the molecule from adding on that second piece, you wouldn't have to worry about splicing it out later. That became the whole philosophy, and both Dr. Collins's group and groups around the world were able to show that happened.

And are the benefits expected to translate into a longer lifespan, and if so, by how much?

This is the fundamental issue that unfortunately we don’t have a good answer for, and so it leaves people somewhat unsettled. Progeria is a disease in which you die over 10 to 15 years, so the problem is that when you treat someone for two years, even when you see some really exciting things, it doesn't prove you have affected their long-term lifespan. The only way you can know that is that you have to do studies long enough to show that short-term turns into long-term. Those studies are going on as we speak, but to say we know the answer wouldn't be fair.

Progeria is extraordinarily rare. Is there any chance these results could translate into benefits for the broader population?

The answer is yes, but again, we have to be very careful. From a theoretical point of view, the answer is absolutely yes for the following reason:

Over the last couple of years, a number of individuals have discovered that — totally a shock to all of us — that all of us, you and me included, are making this abnormal molecule called Progerin. It turns out, when you’ve got the defect built into every single cell, you make it in massive quantities and it starts to damage the blood vessels. Turns out you and I are making it, slowly in minute quantities, every day, day in and day out, which means over a 90-year span, it’s slowly building up.

Researchers for a long time were looking for the biological clock that cells appear to use to tell them when they’re old and it’s time to go away. And the dominant one, it's been known for many years, is telomerase — which is like a little set of beads on the ends of chromosomes, and every time the cell divides, it nips off a couple of beads, and once the beads run out, the sand has gone through the hole, the cell knows it's time to die.

People suspected there had to be other clocks in there as well, and when it was discovered that every human being makes this abnormal molecule — it may be abnormal if you make it in massive quantities with progeria, but you and I make it a little bit at a time, perhaps as a way to educate our cells as to how old they are. So once our cells get enough inside, they begin to stop working and that leads us down the road toward old age and death. Suddenly, it's opened up a whole new opportunity to see if, for example, you could manipulate the small amount made and alter the time course by which cells mature into old age.

We don't know the answers to that, but the little kids who make way too much of it do die of the things that most of us will end up dying of — strokes, cardiovascular disease. And it’s important because only 200 people in the world at any one time have this disease; but billions may have the same process going on. That suddenly opens up opportunities for research and pharmaceutical intervention. Whether they'll pan out remains to be seen.

A Boston Children's Hospital video on the findings:

And the NPR post, including the story of Dr. Leslie Gordon's son, Sam, is here.

This program aired on September 24, 2012. The audio for this program is not available.

Carey Goldberg Twitter Editor, CommonHealth
Carey Goldberg is the editor of WBUR's CommonHealth section.