Mar 2014

Tiny hearts = big deal for drug testing

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When the subject of using stem cells to treat disease comes up, most of us have an image of doctors injecting or infusing these building-block cells into a patient to stimulate the repair of their traumatized tissue or dysfunctional organs.

We’ve written about this approach several times in this space — most recently reporting on a clinical trial to test stem cells in spinal cord injury.  We also reported on a 100-participant study led by Dr. Duncan Stewart at the Ottawa Health Research Institute infusing genetically enhanced blood stem cells into damaged hearts to generate healthy tissue, minimize scarring and prevent heart failure.

Those kinds of studies are called in vivo, meaning “within the living.” But researchers are also opening up entirely different front in the war on disease: using stem cells to create “models” of diseased tissue or organs for testing drugs. Called in vitro (literally, “within the glass” to signify experiments carried out in a Petri dish or test tube), these studies essentially set up a disease straw man for a potential therapy to knock down.

There are advantages to this approach: it skips the pre-clinical animal testing stage that can be a labour-intensive, time-consuming exercise. Imagine the frustration of spending months testing a new drug on rats only to find it’s a no-go. Also, what can show great promise in testing with genetically engineered, immuno-suppressed rats often doesn’t translate into something that will work on real, live, normal human beings.

One of the more promising examples of this kind of work is underway at the University of Toronto’s Institute of Biomaterials & Biomedical Engineering and the McEwen Centre for Regenerative Medicine. Researchers there have developed the first-ever method for creating living, three-dimensional human heart tissue that behaves just like the one pumping blood through your body as you read this. Their findings were published in the Proceedings of the National Academy of Science recently and, so far, have been picked up by 10 media outlets.

“It means basically having hundreds of small versions or models of hearts in one dish, which we can test drugs on to determine which one actually has positive effects,” explains Nimalan Thavandiran, a PhD student in the labs of Drs. Peter Zandstra and Milica Radisic, and lead author of the study.

The ultimate goal, he says, is to create a heart micro tissue that is healthy and then “artificially apply an insult to it” to make it more like a diseased heart. These damaged micro hearts can then be treated with drugs — some that are already on the market for treating other conditions — to see which ones are helpful.

The micro heart tissue can also do service to test the cardio-toxicity of drugs used to treat other conditions. “Often times, a drug to treat cancer will make it to the later phases of a clinical trial and then fail because of side effects on either liver or the heart. So this is why it is important to have human cell-based models, like cardiac or liver models to see early on if these drugs have any adverse effects. And if they do, you can do two things: you can either scrap the drug or you can actually figure out how to molecularly modify it to prevent the toxic effect.”

In the extremely expensive world of drug testing, where it can take hundreds of millions of dollars and many years to test a new drug, having a stem cell-derived micro tissue model represents a huge saving in time, money and resources that could be better spent elsewhere. That’s why many labs across the globe are working to create these models.

With the publication of their paper, Nimalan Thavandiran and his colleagues have shown how to significantly improve the formula for creating stem cell-derived cardiac tissue that behaves like more mature heart tissue. They have come closer than anyone to getting the mix right, factoring in the electrical and mechanical stimulation a heart experiences.

“The heart is consistently both being filled with blood and pumping blood, and so there is a constant mechanical force,” he says. “At the same time, the heart is constantly receiving electrical signals which help maintain synchronicity. All this is very difficult to recreate in a dish.”

They still have further to go, he says. “The ultimate goal is to be able to recreate a perfect micro environment for the heart so that we have an ideal model to screen drugs with.” But they are closing in on what could soon emerge as an important step in drug-testing.

“Until recently, researchers didn’t have the right micro fabrication techniques, the right materials, differentiation protocols, the right understanding of what co-factors are involved with these stem cell-derived heart cells. Now we have a relatively good understanding of all of these things.  It’s just the matter of putting it all together.”

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