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Stem Cells Devised for Rare Disease Boost Personal Medicine

Gabsang  Lee (Johns Hopkins University)

Gabsang Lee (Johns Hopkins University)

Medical researchers at Johns Hopkins University in Baltimore and Memorial Sloan-Kettering Institute in New York developed a method of screening treatments for a rare genetic disorder that the authors say could be applied to tests of stem-cell derived personalized medicines. The team led by Gabsang Lee at the Johns Hopkins Institute for Cell Engineering published its findings online yesterday in the journal Nature Biotechnology (paid subscription required).

Lee (pictured left) began the research a few years ago while a postdoctoral fellow at Sloan-Kettering, with the goal of creating new methods to test for rare genetic disorders. In the earlier research, Lee extracted cells from the skin of a person with a rare inherited disease called Riley-Day syndrome to create induced pluripotent stem cells for developing into the new rare-disease testing methods.

Riley-Day syndrome, also known as familial dysautonomia, occurs most frequently in people of Eastern European Jewish ancestry, and is caused by a mutation in the IKBKAP gene. The symptoms include an inability to feel pain and long episodes of vomiting, and is often fatal. The disease affects one type of nerve cell, which makes it difficult to extract with a biopsy. Lee and colleagues at Sloan-Kettering biochemically reprogrammed the extracted skin cells into induced pluripotent stem cells, which can grow into any cell in the body, in this case nerve cells resembling those from people with Riley-Day syndrome.

In the new research, Lee and colleagues from Johns Hopkins and Sloan-Kettering built on the earlier study by using the same lab-grown Riley-Day nerve cells to test nearly 7,000 small molecule compounds for their effects on these cells. The tests required high-volume robotic screening techniques, which led to the identification of eight compounds that rescued expression of the IKBKAP gene, the gene that in mutated form causes Riley-Day syndrome.

In further testing of the eight hits, one of the small-molecule compounds known as SKF-86466, showed the most promise for stopping or reversing the disease process by inducing IKBKAP gene transcription, the first step of gene expression from DNA to RNA, as well as other favorable properties. Because of the small number of Riley-Day syndrome cases, a full clinical trial of SKF-86466 may not be possible. However, the researchers say the Food and Drug Administration has already approved a highly similar compound for other treatments, which could then be tested with Riley-Day syndrome patients.

Lee believes this approach opens up a potential new process for discovering and testing treatments for rare diseases like Riley-Day syndrome, noting “There are many rare, ‘orphan’ genetic diseases that will never be addressed through the costly current model of drug development.” This process, Lee says, can make it possible to screen for and test compounds not only to treat rare diseases, but also peronalized for individual patients.

Induced pluripotent stem cells could be generated from the reprogrammed skin cells of a patient, from which lab cultures could be made to resemble cells from affected regions of that patient. Treatments could then be tested for safety and efficacy on those personalized lab cultures, with the results helping to determine optimal treatments for the patient. “This approach,” says Lee, “could move much of the trial-and-error process of beginning a new treatment from the patient to the petri dish, and help people to get better faster.”

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