There is renewed hope for treatment of a rare genetic condition that causes rapidly accelerated aging and leads to an average life expectancy of 13 years.
Scientists studying the genes of two infants who died of mysterious illnesses found the infants had mutations in LMNA, the same gene altered in patients with the premature aging condition progeria. But the infants' unusual mutations caused them to make many more bad copies of the gene's primary protein, lamin A, than progeria patients.
Both infants died very young and before researchers could fully unravel the cause of their disorders. But when researchers treated cell samples from one of the patients with a drug targeted for progeria, they saw signs that the cells were improving.
"Our success in treating these cells, which had unusually high levels of bad lamin A, suggest that progeria treatment may not be as distant as we thought," says senior author Jeffrey Miner, Ph.D., associate professor of medicine and cell biology and physiology. "If physicians can reduce production of bad lamin A by as little as half in progeria patients, we might see significant improvement."
Progeria treatment also has potential implications for larger populations. The LMNA gene is involved in several other more prevalent disorders including forms of muscular dystrophy and heart disease.
In addition, recent studies by other labs have shown that occasional errors in the production of lamin A may take place even in people with "normal" copies of the gene. Scientists suspect that accumulation of these bad copies may contribute to aging. If so, treatments that work for progeria patients may one day be adapted to reduce the effects of aging.
The results are published online in the journal Human Mutation.
Science still has much to learn about lamin A. When appropriately produced, the protein becomes part of a meshwork between DNA and the nuclear membrane, which keeps DNA in a pocket known as the nucleus. Lamin A may help arrange the DNA in a way that affects how often genes are used to make proteins.
To get to where it does its job, lamin A binds to another molecule that guides it to the nuclear membrane. Normally the portion of lamin A bound to the guide molecule gets cut off at this point, freeing the rest of lamin A to become part of the nearby meshwork where it belongs.
In most patients with progeria, though, the spot in lamin A where the guide molecule gets clipped off is erroneously deleted during initial assembly of the protein. That leaves lamin A stuck to its guide molecule, which in turn is stuck in the nuclear membrane. Scientists believe this misplacement causes progeria; under the microscope, it leads to visible distortions in the structure of cell nuclei.
By studying the mutations that killed the two infants, Miner and his colleagues acquired new perspective on the mutations in progeria. When they compared how much good and bad lamin A was being made in cells from progeria patients and in cells from the infants, they found the infants' cells were making much more bad lamin A. In addition, they found evidence that progeria patients were making more good lamin A than previously recognized.
One of the two infants was less than a month old at death; the other was 3.5 years old. Given that the infants died so young instead of living for a decade like most progeria patients, Miner concludes that the amount of bad lamin A and the severity of symptoms are linked.
"It's a matter of ratios: the more abnormal protein you have, the more severe the disease," Miner says. "And apparently we don't have that far to go to tip that ratio in progeria patients' favor."
Researchers at other institutions have been developing a treatment for progeria that blocks lamin A from binding to its guide molecule. When lead author Casey Moulson, Ph.D., research instructor in medicine, dosed cells from one of the infants with this drug, the cell nuclei visibly improved.
"If this adds to the impetus for trials of these new drugs, then we may yet be able to bring some good from the tragic deaths of these infants," Miner says.
The Progeria Research Foundation is currently raising funds for a clinical trial of the drug in human patients.