GlaxoSmithKline Plc is applying Shinya Yamanaka’s Nobel Prize-winning discovery in stem cells to identify heart risks linked to experimental drugs earlier in the development process.
Yamanaka was awarded the Nobel Prize in medicine this month for his work in turning ordinary skin cells into induced pluripotent stem, or iPS, cells with the potential to become any cell in the body. That breakthrough has enabled the London-based drugmaker to study iPS cells transformed into heart-muscle cells that may be used to test compounds for cardiovascular safety, said Jason Gardner, head of Glaxo’s early-stage regenerative medicine research.
About half of all experimental drugs fail for safety reasons, and half of those failures are due to toxic effects on the heart, Gardner said. Finding that risk even before animal testing could potentially save drugmakers millions of dollars in clinical-trial costs and better protect patients, he said.
“I call this a low-risk, must-do approach to stem cells,” Gardner said in an interview in Upper Providence, Pennsylvania, where Glaxo has been building on research using iPS cells that began in the U.K. in 2010. “It’s on the verge of being used now for decision-making.”
Other applications include using the test, also called an assay, to help discover new medicines that improve heart function, where there is a “huge need,” he said. The iPS cells can also be used to create motor-neuron cells, aiding development of treatments for conditions such as Parkinson’s disease, and test for drugs’ damage to the nervous system.
At a laboratory in Upper Providence, Glaxo scientists are working with iPS-derived heart-muscle cells supplied from Cellular Dynamics International of Madison, Wisconsin. In a petri dish, individual cells can be seen beating like a heart under a microscope.
The new safety test may bring drugmakers closer to “clinical trials in a dish” and enable them to reduce the number of animal studies, Brian Donovan, an investigator of platform technology science, said during a tour of the lab.
Drug testing may be one of the key applications of Yamanaka’s work, said John B. Gurdon, the British scientist who shared the Nobel Prize with him.
“If you can take cells from a patient, like a patient with a neurodegenerative disease, and grow those in culture in the laboratory, you can test drugs on them easily,” Gurdon said at an Oct. 8 press conference in London. “But you wouldn’t be allowed to test drugs that might have some health implications on the individual, on humans. To be able to derive cells that reflect a disease, in culture, is immensely important.”
Glaxo and its peers have an “ongoing dialogue” with the U.S. Food and Drug Administration as they work to validate the test’s effectiveness, and it will probably be used across the industry within a year or two, especially for development of diabetes and cancer treatments, Gardner said.
While the test will help cut short some drug development, it may also be used to continue with further trials while highlighting any risk uncovered to regulators, Gardner said.
“We get asked a lot, what would Avandia do in this assay?” Gardner said, referring to Glaxo’s diabetes drug. The medicine is no longer sold in Europe and is restricted in the U.S., where it has two black-box warnings about the risk of congestive heart failure and heart attack.
Glaxo has also been collaborating with the Harvard Stem Cell Institute since 2008 to develop commercial medicines. One area that shows promise is in regenerating tissue for muscle wasting, which afflicts the elderly and for which no drugs exist, he said.
While the use of iPS cells for weeding out cardiovascular risk is imminent, transplantation of those cells as treatment will require another three to five years of work in assessing safety, Gardner said.
Scientists at the Riken Center for Developmental Biology in Kobe plan to use iPS cells next year in a trial among patients with macular degeneration, a disease in which the retina becomes damaged, resulting in loss of vision, Yamanaka told reporters in San Francisco Oct. 8.
“The next two to three years will be incredibly exciting,” Gardner said. “This is a renaissance for stem cell science.”