January 28, 2013
New Disease-in-a-Dish Model Could Lead To New Treatments For Rare Heart Condition
redOrbit Staff & Wire Reports - Your Universe Online
For the first time ever, researchers have been able to develop a maturation-based “disease-in-a-dish” model for an inherited heart ailment — a discovery that will help researchers study and test new therapies for the condition.
Patients suffering from the condition, which is known as arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), typically do not become aware that they have a heart problem until they are in their early 20s, researchers from the Sanford-Burnham Medical Research Institute said Sunday in a statement.
Because symptoms take so long to surface, it has typically been difficult for the medical community to analyze the disease, or to find ways to treat it. Now, however, Sanford-Burnham researchers, along with colleagues from Johns Hopkins University, have used a stem cell-based technology that allowed them to create heart muscle cells from a patient´s own skin tissue in the hopes that they could better understand ARVD/C.
The research, which is detailed in Sunday´s edition of the journal Nature, took the stem cell-based technology developed by 2012 Nobel Prize winner Dr. Shinya Yamanaka, then used a new method that allowed them to mimic maturity by making the metabolism of the cells similar to that found in an adult´s heart, since ARVD/C symptoms tend not to surface in younger individuals.
By combining Yamanaka's technology and the new cell metabolism mimicry method, the researchers were able to create a model they believe will be “more relevant to human ARVD/C than other models and therefore better suited for studying the disease and testing new treatments,” Sanford-Burnham researchers wrote.
"It's tough to demonstrate that a disease-in-a-dish model is clinically relevant for an adult-onset disease,” added senior author Dr. Huei-Sheng Vincent Chen, an associate professor at the research institute. “But we made a key finding here–we can recapitulate the defects in this disease only when we induce adult-like metabolism. This is an important breakthrough considering that ARVD/C symptoms usually don't arise until young adulthood. Yet the stem cells we're working with are embryonic in nature.”
Assisting Chen in the development of the model was Drs. Daniel Judge, Joseph Marine, and Hugh Calkins, cardiologists and ARVD/C experts affiliated with the Baltimore, Maryland private research university. Judge explains that while there is currently no way to prevent progression of the rare disorder, the new model could help doctors and other medical experts ultimately develop ways to help battle this life-threatening condition.
To create the models, Chen and colleagues started by obtaining skin samples with ARVD/C patients who they believed had specific mutations that could be linked to the disease. Then, they applied Yamanaka´s technique to turn them into induced pluripotent stem cells (iPSCs), before coaxing them into producing an unlimited amount of heart muscle cells that were specific to the patient from which they had originally been drawn.
“These heart cells were largely embryonic in nature, but carried along the original patient's genetic mutations,” the researchers explained. “However, for nearly a year, no matter what they tried, the team couldn't get their ARVD/C heart muscle cells to show any signs of the disease. Without actual signs of adult-onset ARVD/C, these young, patient-specific heart muscle cells were no use for studying the disease or testing new therapeutic drugs.”
Ultimately, they came to the realization that the cells needed to reach a state of metabolic maturity in order for signs of the condition to arise. The key difference is in the source of energy for immature or adult cells — embryonic-like cells prefer glucose, while adult heart muscles prefer using fat. After creating simulated adult metabolism in the cells used for their model, the researchers discovered that a “metabolic malfunction” was the key to the disease.
“Moreover, Chen's team tracked down the final piece of puzzle to make patient-specific heart muscle cells behave like sick ARVD/C hearts: the abnormal over-activation of a protein called PPAR,” the statement said. “Scientists previously attributed ARVD/C to a problem in weakened connections between heart muscle cells, which occur only in half of the ARVD/C patients. With the newly established model, they not only replicated this adult-onset disease in a dish, but also presented new potential drug targets for treating ARVD/C.”