Advancing Use of Stem Cells in Personalized Medicine
Johns Hopkins researchers report concrete steps in the use of human stem cells to test how diseased cells respond to drugs. Their success highlights a pathway toward faster, cheaper drug development for some genetic illnesses, as well as the ability to pre-test a therapy's safety and effectiveness on cultured clones of a patient's own cells
The project began several years ago, when Gabsang Lee, D.V.M., Ph.D., assistant professor at Johns Hopkins University School of Medicine's Institute for Cell Engineering, was a postdoctoral fellow at Sloan-Kettering Institute in New York.
The work was published November 25, 2012 in Nature Biotechnology.
To see if induced pluripotent stem cells (iPSCs)
could be used to make specialized disease cells for
quick and easy drug testing, Lee and colleagues
extracted skin cells from a person with a rare
genetic disease called Riley-Day syndrome,
which affects only one type of nerve cell
that is difficult if not impossible to extract
directly from a traditional biopsy.
These traits made Riley-Day an ideal candidate for alternative ways of generating cells for study.
In a so-called "proof of concept" experiment, researchers biochemically reprogrammed the skin cells from the patient to form iPSCs, which can grow into any cell type in the body. The team then induced the iPSCs to grow into nerve cells.
"Because we could study the nerve cells directly, we could for the first time see exactly what was going wrong in this disease," says Lee. Some symptoms of Riley-Day syndrome are insensitivity to pain, episodes of vomiting, poor coordination and seizures; only about half of affected patients reach age 30.
In the recent research at Johns Hopkins and Memorial
Sloan-Kettering, Lee and his co-workers used these same
lab-grown Riley-Day nerve cells to screen about 7,000
drugs for their effects on the diseased cells.
With the aid of a robot programmed to analyze the effects,
the researchers quickly identified eight compounds for
further testing, of which one SKF-86466
ultimately showed promise for stopping or reversing
the disease process at the cellular level.
Lee says a clinical trial with SKF-86466 might not be feasible because of the small number of Riley-Day patients worldwide, but suggests that a closely related version of the compound, one that has already been approved by the U.S. Food and Drug Administration for another use, could be employed for the patients after a few tests.
The implications of the experiment reach beyond Riley-Day syndrome, however. "There are many rare, 'orphan' genetic diseases that will never be addressed through the costly current model of drug development," Lee explains. "We've shown that there may be another way forward to treat these illnesses."
Another application of the new stem cell process could be
treatments tailored not only to an illness, but also
to an individual patient.
That is, iPSCs could be made for a patient, then used
to create a laboratory culture of pancreatic cells,
in the case of a patient with type 1 diabetes.
The efficacy and safety of various drugs could then be
tested on the cultured cells, and doctors could use the
results to help determine the best treatment.
"This approach 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," says Lee.
Other authors of the paper are Christina N. Ramirez, Ph.D., Nadja Zeltner, Ph.D., Becky Liu, Constantin Radu, M.S., Bhavneet Bhinder, Hakim Djaballah, Ph.D., and Lorenz Studer, Ph.D., of the Sloan-Kettering Institute; and Hyesoo Kim, Ph.D., Young Jun Kim, M.D., Ph.D., InYoung Choi, Ph.D., and Bipasha Mukherjee-Clavin of the Johns Hopkins University School of Medicine.
The work was supported by funds from New York State Stem Cell Science (NYSTEM), the New York Stem Cell Foundation (NYSCF), the state of Maryland (TEDCO, MSCRF), the Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center at Memorial Sloan-Kettering Cancer Center, the William Randolph Hearst Fund in Experimental Therapeutics, the L.S. Wells Foundation, and the National Cancer Institute (grant number 5 P30 CA008748-44).