TUESDAY, Sept. 27, 2005 (HealthDay News) -- In what researchers are calling an "extremely lucky" discovery, a class of drugs already well-tested for safety in cancer patients may also fight a rare, fatal children's disorder characterized by accelerated aging.
In progeria -- which strikes just one in every 4 million children -- a single genetic mutation triggers conditions typically associated with advancing age. Children with the illness begin to develop skin and joint problems, as well as clear signs of cardiovascular disease, and most die from heart-related problems before reaching 20 years of age.
But recent announcements in five separate scientific papers that a class of drugs called farnesyltranferase inhibitors (FTIs) might prevent the cellular flaw behind progeria is finally giving these children reason to hope.
While there's never any guarantee that what works in the lab will work in patients, "this is our best hope in the short-term for these kids," said Dr. Leslie Gordon, a progeria researcher and co-founder (with her husband, Dr. Scott Berns) of the Progeria Research Foundation, which helped fund all of the studies.
Gordon and Berns are more than just doctors and researchers, however: Their 8-year-old son, Sam, was diagnosed with progeria when he was just 3 years old.
That diagnosis changed the course of their careers, which have been devoted ever since to raising funds for, and supporting, progeria research.
Largely because of the foundation's efforts, scientists have already identified the cause of progeria (mutations in a single gene), set up a tissue bank necessary for ongoing research, and organized regular scientific meetings to exchange ideas. The foundation is also working with the National Institutes of Health to collect data on children with progeria worldwide, as a baseline dataset for their ultimate goal: clinical trials aimed at a cure.
And now, the first hope for a treatment to fight the root cause of the disease has come.
Writing in this week's issue of the Proceedings of the National Academy of Sciences, a team led by Johns Hopkins University researcher Susan Michaelis say that FTI drugs appear to prevent or reverse -- in cell cultures -- the cellular defect that drives progeria.
The key molecule under investigation is a protein lying near the cell's nucleus, called lamin A.
"Normally, lamin A goes through a complicated set of modifications before it reaches its final form," said Michaelis, a professor of cell biology at the university.
During part of this process, a lipid molecule group called farnesyl gets attached to one end of the protein, only to be snipped off again.
But in progeria, the gene mutation that triggers the disease "blocks that last cutting-off of this modification," she said. "So you end up with a molecule that still has this lipid modification on it, when it really should have been cleaved away."
That tiny bit of extra lipid locked at the end of the lamin A protein somehow "gums up the works" inside the cell, Michaelis said. And for reasons that remain unclear, it can trigger systemic, rapid aging of the type seen in progeria children.
But as soon as scientists discovered the genetic mutation that leads to progeria, they also began to focus on the FTI group of cancer drugs as possible treatment.
"We immediately thought about it," Michaelis said. That's because her lab was the first to identify the enzyme responsible for cleaving farnesyl from the lamin A protein.
And in this latest work, her group confirmed that FTIs effectively inhibit farnesyl from latching onto the end of lamin A in the first place, preventing the progeria-linked defect.
Four other recently published studies -- one co-authored by Gordon -- have reached similar conclusions.
Still, Michaelis remains cautious.
"We know that at a cellular level, FTIs disrupt or reverse that [defect]," she said. "But that's long way from knowing what effect it's going to have in a person, and in a person with this disease."
Gordon agreed. "I don't want to oversell this," she said, noting that the drugs, though generally found to be of low toxicity in non-progeria patients, will not immediately be tested in children with the disease.
"We need to take some steps first to convince ourselves that it's going to be safe in children with progeria," she said. To that end, research is being directed to the creation of a "designer" mouse -- a genetically engineered mimic of progeria that can be used to test FTIs in an animal model.
In the meantime, the foundation continues to fund research on other fronts -- in gene therapy, for instance, and in treatments that might fight the more "downstream" effects of the disease.
But Gordon remains hopeful that FTIs will prove safe, effective and ready for use against progeria within the next few years. "We're lucky, because a lot of the toxicity testing has been done [in cancer patients], and we just need to do a little bit more before we can move forward and ask drug companies and the FDA for their approval," she said.
Right now, lab studies suggest that FTIs are effective against a major form of the disease, called Hutchinson-Gilford progeria syndrome, the type affecting Sam Berns. "But they have the earmarks of possibly being applicable to the other forms," Gordon said.
In the end, the discovery that a compound already in the pharmaceutical pipeline and well-tested for safety may fight progeria "is incredible," she said. "It's what we dreamed of when we started this. It's like the stars aligned just for us, and all we need to do now is just start pushing forward."
More information
For more on progress against progeria, head to the Progeria Research Foundation.
