Leslie Gordon: Progeria learns from aging; aging learns from progeria
Children with progeria have a genetic mutation that makes them physically age very rapidly. They develop atherosclerosis and die of heart attacks or strokes at an average age of 13 years. Leslie Gordon, research associate professor of pediatrics in the Warren Alpert Medical School and on staff at Hasbro Children’s Hospital, has marshaled a research effort that in the span of a decade has advanced the field from a state of virtually no biological knowledge to a potential treatment. Gordon’s passion to defeat progeria is both professional and personal: Her 14-year-old son, Sam, is a happy Boy Scout with a flair for engineering who is living with the disease.
Seven years ago the Progeria Research Foundation that you co-founded helped to discover the mutation. Where did that advance lead?
We started by forming a consortium in 2002, a team of scientists who would lead a search for the gene mutation causing progeria. Within less than a year of forming the PRF Genetics Consortium with some amazing scientists [including Francis Collins], team members discovered the mutation responsible for progeria in a gene called LMNA. It codes for a protein called lamin A. The faulty lamin A produced by the mutation is called progerin. Lamin A is an “inner nuclear membrane” protein that is responsible for normal cell structure and cell function. We knew a lot about lamin A, and we transferred that knowledge to understanding how progerin acts as a lamin A imposter to cause damage to cells.
We went from the gene discovery to enough of an understanding about the pathobiology involved with that mutation to arrive at a potential treatment, test that treatment on cells in the laboratory, and test that treatment on mice. We then moved into human clinical trials that began in May 2007.
What is the status of the clinical trials?
The first trial tested an agent called a farnesyltransferase inhibitor. We used a drug called lonafarnib, which is a made by Merck. Farnesyltransferase inhibitors were created to fight cancer, and now we have repurposed that drug for use in progeria. Our hypothesis was that a farnesylation inhibitor might be useful because a farnesyl group allows the attachment of progerin into the inner nuclear membrane of cells where it is doing a lot of its damage. Patient visits for that trial ended about a year ago, and we are in a process of full data analysis.
Most of those patients plus an additional 19 patients — 45 patients total — then started on another trial. We call it the triple-drug trial, in which we hopefully are embellishing the effects of the farnesyltransferase inhibitor with two additional drugs that address the same pathway. We are in the middle of that trial now at Children’s Hospital in Boston.
This summer you published a study showing a connection between progeria and heart disease in adults. What was that?
We can learn a lot about progeria from aging, and we can learn a lot about aging from children with progeria. Progeria is a pure cause of cardiovascular disease. Children with progeria don’t smoke, family history doesn’t really play a big role, and they don’t have high cholesterol. Therefore, we can ask what effect progerin has on heart disease in children with Progeria, and on heart disease that affects millions of aging people around the world.
We discovered that there is tremendous overlap between the two, including the presence of progerin in cells of adults without progeria. We all make a little bit of progerin. Even more striking was our finding that the amount of progerin in the cells of blood vessel walls increases as we age.
What is life like for a child with progeria?
They are usually born looking normal but soon thereafter there is “failure to thrive,” which is falling off the growth curve. By the age of 2 to 3, they’ve only got this light, downy hair left and they lose body fat. But children with progeria are intellectually right on target. They are funny and smart and wonderful to be around, and usually don’t have any trouble making friends. Many times children with progeria will go to public school with some accommodations, like many children have.
They have all the energy of other kids for the most part, but later [usually in their teens] the children start to run into trouble with things like strokes and heart attacks, cardiovascular disease that eventually leads to their passing away.
How is Sam doing?
Sam’s in eighth grade. He really enjoys school. He goes to public school. We’re blessed and truly fortunate that Sam is a happy, wonderful boy and he’s doing very well. He’s in a Lego robotics club. He does Invention Convention. He was on the math and science team last year. He’s been on student council for a few years. Sam is also involved in the Boy Scouts. He wants to be an Eagle Scout very badly. He’s working very hard on that.