Urbach and co-first author Ori Bar-Nur, a graduate student in Benvenisty's lab first created fragile X iPS cells from the skin cells of two affected patients and related lung cells from a 22-week-old fetus with fragile X, testing them extensively to assure themselves and other researchers of their stem-cell qualities. They also investigated why the FMR1 gene remained stubbornly locked down.

"We show the reason the gene is not expressed is because it still has the epigenetic markers for silencing," Urbach said.

The fragile X gene may be one of the first genes to resist the reprogramming process that transforms adult tissue cells into iPS cells, but it's likely not the last, said the researchers.

"This raises a general caution for using iPS as a faithful reflection of a disease process," Daley said. "There are lots of conditions where you have gene defects that lead to gene silencing. Such conditions may not be faithfully modeled by iPS cells. Fragile X is a disease where using embryonic stem cells as a tool is essential."

The differences in the iPS and embryonic fragile X stem cells make them useful for different types of studies, the researchers say. "On one hand, iPS cells are not as good for modeling the inactivation of the gene," Benvenisty said. "On the other hand, they may be a better model for studying neurons lacking expression of the gene."

"New insights into fragile X have stimulated clinical trials of drugs that block the overactive excitatory receptors in nerve cells," Daley said. "Early results hint that these drugs might ameliorate the condition of fragile X. With our stem cell models-diseases in a dish, if you will-we can test whether the drugs will reverse abnormal connections at the synapses that we think are at the basis of this condition. If your goal is blocking FMR1 gene silencing, you're better off working on drug screens in embryonic stem cells than in iPS cells."

Source: Children's Hospital Boston