Embryonic Stem Cells in Trial for Diabetes

As San Diego’s ViaCyte was in the midst of launching the first FDA-approved embryonic stem (ES) cell clinical trial for diabetes last week, Boston’s Harvard University reported that beta cells made from ES cells “cured” diabetic mice.

Both teams worked for years to painstakingly recreate the natural development of pancreatic islet cells— if Harvard took it further in the dish, and ViaCyte took it further to the clinic.

“A remarkable tenacity has been displayed by these two teams, on opposite sides of the country,” said Scripps Research Institute ES cell expert Jeanne Loring by email to Bioscience. “Both should be congratulated. This is a notable moment in the history of human stem cell research— I would dare to hope that it’s the beginning of the golden age of stem cell therapeutics. Diabetes has been an important target for stem cell therapy. Ever since islets from cadavers were first transplanted in the 1990s (the Edmonton Protocol) it’s been clear that a better source of islet cells would be the key to real long term therapeutic benefit.”

The better source appears to have been found, she said, if “we still can’t use the word ‘cure.’”

Harvard’s ‘extraordinary’ pre-clinical work

The “c-word” can be used with regard to animal models, however, Melton feels, also talking to Bioscience via email. After 15 years of work, systematically testing 150 different combinations of more than 70 compounds involved in pancreas development, his team finally created mature islet cells— from both human ES cells, and human induced pluripotent stem cells (iPSCs, pluripotent cells made from mature cells).

The recipe, as published in Cell, was 11 compounds, applied in a carefully timed fashion for four weeks.

“The cells we make respond to glucose and secrete insulin, and do so multiple times,” said Melton, a father of two children with diabetes. “When our cells are transplanted into mice, they ‘cure’ the mice in a few days.”

Cadaver islet cells are rare, and only last up to five years. By contrast, Melton’s ES and iPS cells are robust, and can make billions of copies of themselves. His cells do need to be placed in a yet-to-be-devised capsule, to protect them from the immune system, and contain them should they go awry.

But the field has reacted with alacrity.

“The new study of Doug Melton is a true milestone in the use of pluripotent stem cells in diabetes,” Hebrew University Stem Cell Unit Director Nissim Benvenisty told Bioscience via email. “The generation of pancreatic beta cells was an elusive target in the past decade. The new study demonstrates an efficient methology for generating the cells, and shows many of the characteristics of authentic beta cells both in vitro and in vivo.”

Emailed Tim Kieffer, a University of British Columbia expert in stem cells and diabetes: “I congratulate Dr. Melton’s team for this work.”

Even the head of Harvard, Drew Faust, weighed in. In a statement emailed to the press he said he was “excited” by the “extraordinary” work.

“I’m very happy for Doug," said Loring. “He’s been working on this a very long time, and had to start from the beginning again and again. This seems to be the inevitable requirement for figuring out how to differentiate human pluripotent stem cells. By using what is known about embryonic development of the pancreas, and applying that knowledge to cells in culture dishes, Melton’s team was able to coax human ES cells into becoming pancreatic islet cells that are very similar to the cells in our bodies.”

ViaCyte’s ‘careful’ clinic-ready approach

Still, she noted, Melton has competition. ViaCyte “started working toward the same goal of treating diabetes with human ES cell-derived islets more than 10 years ago. They published their method for making islet cells— less mature than the ones made by Melton’s group— nearly eight years ago, and they worked for many years on designing a device to deliver the cells to the body that would allow them to thrive and not be rejected as foreign cells.”

Indeed, they recently received FDA approval to implant their cells, in patients, in a teabag-like implantable device. They will transplant the cells at a more immature stage than Melton’s, as they found they “worked better” if allowed to mature post-transplant, in the bodies of lab animals— and soon, people. “This careful approach got them FDA approval,” said Loring.

Melton said “the progenitors ViaCyte makes do not respond to glucose [in that earlier stage], and when differentiated in the dish, they report the cells express more than one hormone, they are polyhormonal.” (Melton’s final cells, as noted, repeatedly respond to glucose, and make only the hormone regulating it: insulin.)

Furthermore, he said, while his cells “cure” mice in days, “their cells ‘cure’ mice in a few months,” as they need the host metabolism to finesse differentiation, and persuade the cells to respond to glucose, i.e., get to work.

Speaking to Bioscience by interview and email, Viacyte CEO Paul Laikind and CSO Kevin D’Amour said their more immature cells do not respond to glucose in vitro, but said that they do in vivo. They also noted that their cells take less production time ex vivo: two weeks to Melton’s four. Their cells are equally scalable, they said. They believe the heterogeneity of their cells may be an asset, mimicking earlier developmental environments, keeping them happy in their “teabag” niches.

But they also settled on that immature state years ago, they said, because accessible spots just under the skin for ideal placement tend to be hypoxic, a condition progenitors tolerate better than mature cells.

“Our stepwise changes also mimic the developmental biology of the pancreas,” said D’Amour. He noted Melton’s work built on theirs, as Melton stated in his paper.

But the biggest difference right now may be the fact that ViaCyte is in trial, while Harvard plans to finish a capsule, and try cells in primates first.

“We are screening our first patient now, as we speak,” said Laikind. “We expect to implant the cells in the next couple of weeks.” Forty patients will be treated in ViaCyte’s Phase 1 trial.

Even more competition

Both groups noted there is more game in town: BetaLogics, which came out with a paper in Nature Biotechnology four weeks ago describing similar pre-clinical success with ES cells for diabetes.

Both BetaLogic and ViaCyte have agreements with Johnson & Johnson.

Aside from diabetes, ES cells are also in trial for macular degeneration, and are headed for trial in heart failure.

Video courtesy Harvard Univesity/Mikey Segel.