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Cellular Defects in Premature Aging Disease are Reversible

anent or reversible," said Scaffidi. First, the investigators added DNA encoding normal lamin A into cells taken from patients affected with progeria, but observed that increased synthesis of normal lamin A did not correct any of the progeria-associated defects. In addition, they found that introduction of the mutant protein into healthy human cells was sufficient to produce the disease characteristics. "These results made it clear that in order to achieve a potential therapeutic effect, we needed to completely eliminate the mutant protein," said Scaffidi.

The NCI researchers designed a chemically stable DNA oligonucleotide ?a short DNA sequence that the cell wouldn't be able to degrade ?that would bind to the mutant splice site and prevent the splicing machinery from cutting in the wrong place. "You can think of it as a molecular Band-Aid®," said Misteli. The researchers inserted their oligonucleotides into the progeria cells and observed that after four days almost all the mutant lamin A transcripts had been eliminated and replaced with the properly spliced counterpart. The oligonucleotide was highly specific to the mutated region and did not cover-up other splicing locations. One week after correcting the splicing defect, the mutant lamin A protein had been eliminated and more than 90 percent of progeria cells were restored to normal; visually, the nuclei lost their wrinkles and lobes and returned to a natural ellipsoid shape, and the expression of other nuclear proteins was also restored to normal levels.

"It's amazing that we could take a cell that looked about ready to die, and a few days later it was healthy and ready to divide again," said Misteli.

Misteli noted that these results demonstrate a proof-of-principle that the cellular effects of progeria can be reversed, meaning his laboratory's method could be used some day in the future as a therapeutic strategy. The fact that a progeria reversal can be achieved in multiple cell types,
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Source:NIH


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