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Drug Helps Stem Cells Turn Deaf Ear to Allure of Eternal Youth

By Anette Breindl
Science Editor

Many of the scientists who are attempting to harness stem cells for tissue repair and regeneration do so via a transplantation approach.

That pathway consists of finding a source of stem cells and transplanting them. The stem cells themselves might be transplanted, or they might be coaxed into the desired mature cell type or something on the pathway to it first.

Either way, it is a transplantation approach. But another possibility is to identify small molecules that stimulate the body's own stem cells to divide. Even though their absolute numbers do decline over the course of a lifetime, such an approach remains feasible for many indications in adults, including the elderly adults who are most likely to need it. "There are plenty of stem cells available in most human tissues, even at an advanced age," John Cashman told BioWorld Today.

Cashman is a co-author on several papers that describe a small molecule that can guide stem cells to develop into cardiomyocytes or heart cells. Or perhaps, the better description is that it removes a block on development that allows stem cells to take their natural trip down the road to heart cells.

The molecule, ITD-1, works by blocking the signaling of transforming growth factor beta, or TGF-beta. TGF-beta signaling usually keeps a brake of sorts on heart stem cells, preventing them from developing into mature heart cells and keeping them in a more pluripotent state instead. Cashman and his colleagues discovered that when ITD-1 bound to TGF-beta receptors, those receptors were targeted to the proteasome and destroyed instead of staying in the more typical cycle of binding, internalization, releasing its ligand, and recycling back onto the cell membrane caused by binding TGF-beta itself.

As a result, TGF-beta signaling falls on deaf ears in stem cells that have been treated with ITD-1. And that in turn removes the brakes on their developing into heart cells – a process that TGF-beta normally inhibits.

Cashman is both president and founder at the Human Biomolecular Research Institute and the CEO of start-up ChemRegen Inc.

ChemRegen is a joint spinout of the Human Biomolecular Research Institute and the Sanford-Burnham Medical Research Institute and, like its parent institutions, is located in San Diego. The company was founded in 2009, is funded via SBIR grants, and working in the areas of cardiovascular disease and cancer.

Cashman said that the "most compelling aspect" of the company's work is to deliver small-molecule drugs that can stimulate stem cells directly to the heart, for example, via a catheter or stent. Such delivery, they hope, would be an alternative to transplanting the cells themselves.

Cashman argued that giving small molecules to activate endogenous heart stem cells "in principle is much safer and much less toxic than delivering cells."

While stem cells, or gene therapy, literally take on a life of their own with treatment – indeed, that's the point – small-molecule activators "don't carry any long-liver information, so to speak."

Not that ChemRegen is necessarily averse to cell delivery approaches. In fact, the company is also using its technology to try and create large numbers of cells for transplantation, as well as for screening purposes.

The experiments on stem cell-targeting drugs have also led, unexpectedly, to the identification of compounds with robust anticancer activity, and ChemRegen is working on developing that area of its business.

The findings have not been published yet, and Cashman gave only vague explanations of that part of ChemRegen's work. Whether the compounds affect specifically cancer stem cells is not clear. But Cashman said that the compounds could have very broad utility, both because they appear to synergize with many existing cancer drugs and because they are active in several different tumor types.

Cashman said that the company's ability to venture into the cancer field demonstrated the quality of the company's collaborations with the Human Biomolecular Research Institute and Sanford-Burnham Medical Research Institute. "We're really novices in cancer," he acknowledged. The company, he added, is going where the data are leading it – and its ability to do so is a testament to the "the interdisciplinary approach, and the strength of the collaboration."