Old drug offers new hope against disease
Blake Althaus, 5, has thrived on an experimental treatment. (Boston Globe Photo / David Ellis)
Blake Althaus wasn't expected to live much past his second birthday.
A genetic disorder was weakening muscles throughout his body, as well as his aorta, the main artery from his heart - leaving him lethargic and nearly immobile.
Then a Baltimore researcher following a medical hunch, discovered that a years-old blood pressure medication seemed to reverse the symptoms of his disease, known as Marfan syndrome. Children with severe Marfan - a disorder of the connective tissue, the structural stuff that holds the body together - often have very small, weak muscles and elongated limbs, in addition to damaged aortas.
Now 5, Blake is in his third year of receiving the drug losartan and is energetic enough to go to school, play with friends, and ride his "Big Wheel" tricycle.
Though still in early stages of research, losartan is showing promise in treating more than a dozen other children with severe cases of Marfan, and will soon be tested against a more common inherited muscle-wasting disease, muscular dystrophy.
"It's important because it seems to repair [muscle tissue] a bit better," and cause fewer side effects in animal experiments than the current treatment for muscular dystrophy, said Dr. Louis Kunkel, a Howard Hughes Medical Institute pediatrician and geneticist at Children's Hospital Boston. So far, there have been no human trials of the drug in muscular dystrophy patients.
Dr. Harry Dietz at Johns Hopkins Medical School in Baltimore, identified the mutant gene that causes Marfan several years ago. But the pediatrician was still frustrated by the lack of progress against the disease, which can also cause heart valve defects and lung and eye problems.
No one could see why such complex problems stemmed from a single genetic mutation that damaged connective tissue, nor how to treat them.
"It was a time of great pessimism," Dietz said. "How could you give something that's missing in every tissue? It was like a house built with a rotten frame."
In what Dietz recalls as an "epiphany moment," he entered a young patient's room, looked at those long bones, and thought, "this just doesn't make sense . . . You couldn't explain those [elongated] fingers just with weakness of the tissues."
Back in the lab, he realized that the defective gene he had discovered was triggering overproduction of a tissue growth factor called TGF-beta. TGF-beta, a protein, tells cells how to behave, so its overproduction could explain how so many things go wrong in people with Marfan.
"We really believe we have a fundamental new understanding of Marfan syndrome," he said.
Normal muscles can repair themselves when injured by, say, running a few miles. But the muscles of people with Marfan, because they have too much TGF-beta, cannot self-repair, the team discovered - a problem also common among other muscle "wasting" disorders such as muscular dystrophy.
By blocking activity of TGF-beta in specially bred mice, Dietz's team was able to normalize many of the defects and then went looking for a drug that might do the job in people. Losartan, the blood pressure drug, had a known side effect of blocking TGF-beta. They tried it on the mice, and it worked.
Dietz received "compassionate use" permission from his hospital to give the oral drug, made by
Blake's mother, Anita, said that before the losartan treatment began, her son's aorta was expanding dangerously, threatening rupture. But after three months on the drug, "for the first time, there was no change" in the aorta's size. "Our pediatrician said it was coincidence." But after it remained stable in three subsequent tests, "he said, 'I'm on board, fully.' "
Since then, Dietz said, "we've now treated 19 severely affected children," and the results have been encouraging. But he warned that doctors shouldn't switch Marfan patients off current treatments - which do some good - until losartan is better understood.
There are now 604 Marfan patients, ages 6 months to 25 years, being recruited for a three-year national trial of losartan's impact on aortic weakening. Doctors also hope to monitor the same patients - half on losartan, half on a different blood pressure drug, atenolol - for changes in their lungs, bones, muscles, and eyes.
Marfan syndrome is relatively common among inborn genetic disorders, seen once in every 5,000 live births, according to the National Marfan Foundation. Its severity varies enormously among patients, ranging from barely noticeable - some people don't even know they have it - to complete disability and early death.
As for Blake, "I can barely keep up with him," his mother said.
Still, surgery is being scheduled soon to implant adjustable rods to keep his spine in alignment and control scoliosis, a curvature of the backbone. Dietz said he suspects Blake and the other Marfan patients will need to take losartan for the rest of their lives.
"It won't entirely cure Marfan," he added, "but we hope it will radically change the [patients'] quality of life."