FD patients are known to have a mutation in a gene that encodes a protein called IKAP. The mutation causes part of the genetic sequence to be skipped when the gene is translated into a protein; however, the genetic defect only affects certain tissues, for reasons not known. To understand more about the disease, the researchers looked for the normal and mutated protein in the different cell types. Studer says they expected that the neural cells would have more of the abnormal protein. But in fact, they found that the faulty translation happened at equal rates in the different types of cells. Levels of normal IKAP were much lower in the neural cells, which may be why the disease strikes these cells.
The team also found that the cells were defective in their ability to differentiate into neurons and did not migrate as easily as normal cells in a culture dish. The researchers used these differences to measure the effect of three drugs that had been proposed as candidate drugs for FD. One of them, kinetin, a natural plant hormone that is often used as an antiwrinkle treatment in cosmetics, showed promise in treating the cells When cells were treated with the drug, Studer says, “it led to near complete reversal of the splicing defect.” Further treatment reversed the defect in differentiation, although it did not affect the cells’ ability to migrate.
Susan Slaugenhaupt, a neurologist at Massachusetts General Hospital who studies FD, says that these cells help alleviate a long-standing frustration in studying neurological disease. This technology provides “the ability to examine disease-relevant cell types from patients” for the first time, she says. “You can’t get brains from patients and look at these cell types.” Slaugenhaupt is now collaborating with the research team to further test drugs for FD using this model.
Slaugenhaupt adds that this study is the first to show that kinetin can improve disease in neural cells and that it “provides the best evidence to date that long-term treatment with kinetin may be beneficial to FD patients.” Clinical trials of the drug are scheduled to start soon.