Sci. Aging Knowl. Environ., 15 December 2004
Ignorance Is Bliss
Treatment makes cells from people with premature aging disorder overlook genetic abnormality and behave normally
WASHINGTON, D.C.--Like a living room wall with holes that have been plastered and painted over, cells from people with a premature aging disease can look normal again when the product of the culprit gene is fixed, according to research presented here 6 December 2004 at the American Society for Cell Biology Annual Meeting. The results verify the idea that the faulty protein prevents the normal one from doing its job and provide clues to possible therapy.
People with Hutchinson-Gilford progeria syndrome (HGPS) gray and wrinkle while they're children and die in their teens of scourges such as heart disease that typically affect much older individuals. Alterations in the lamin A gene cause the disease. Lamin A protein supports and shapes the cell's nucleus, and the most common mutation creates an inappropriate splice site, resulting in a messenger RNA (mRNA) that produces a shortened protein. People with one defective copy of lamin A and one normal copy suffer from HGPS, suggesting that the clipped protein somehow interferes with the normal copy's function. However, patients also have reduced amounts of the normal protein in their cells, so Scaffidi and Misteli wondered whether restoring its abundance would ameliorate the disease.
To explore this possibility, the researchers overproduced normal lamin A in skin or immune system cells from people with HGPS. The cells looked as sickly as ever, missing particular proteins and containing bulbous nuclei. This result suggests that the mutant form dominates over the normal form and that supplementary healthy protein doesn't rescue the cells. Then they injected snippets of special DNA that helps cellular machinery ignore the problem site that generates the lopped mRNA. Amounts of regular-sized lamin A protein rose almost up to those in healthy people, and the shortened version wasn't detectable. After 4 days, the majority of misshapen nuclei had smoothed out. Then the researchers gauged the activity of a handful of genes that are over- or underactive in sick cells; the treatment readjusted their quantities to proper amounts.
"It was really striking how well the treatment rescued the cells," says cell biologist Katharine Ullman of the University of Utah, Salt Lake City. She adds that Scaffidi and Misteli are "laying the groundwork for therapeutic intervention." A technique that similarly fixes a misplaced splice site shows promise in mouse models of a potentially fatal anemia called beta thalassemia, providing hope that the general strategy will work. Cell biologist Brian Burke of the University of Florida, Gainesville, says the work is "a proof of concept that you can--quote-unquote--cure cells." The treatment "may provide a valid approach" to treating HGPS if the significant obstacles to delivering the therapy to cells in living people can be overcome. Perhaps someday practitioners will be able to paint over the genetic blemishes that make some people seem old before their time.
December 15, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150