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September 19, 2017

Cell-Centered: Scientists Embrace Cell-Replacement Therapy for Type 1 Diabetes

Forming Beta Cells from Stem Cells

Cell-Centered: Scientists Embrace Cell-Replacement Therapy for Type 1 Diabetes

Source: Getty Images/Sakra

  • A century ago, type 1 diabetes was a death sentence. Now, it’s a daily struggle. When blood sugar soars, diabetics risk damage to their eyes, kidneys, and nerves. And when blood sugar dips too low, vital organs like the heart and brain shut down, leading to lightheadedness or even coma.

    Normally, the pancreas regulates blood sugar. A special population of cells, known as beta cells, make insulin, which helps the body soak up excess blood sugar after a meal. In type 1 diabetes, the immune system kills these cells. To compensate, patients inject themselves with insulin and check their blood sugar levels before and after meals.

    It’s a stressful task, though recent advances have helped. The major insulin makers — including Sanofi, Novo Nordisk, and Eli Lilly — offer slow- and fast-acting insulins to help patients control their blood sugar throughout the day. And in 2016, the FDA approved the first ‘artificial pancreas,’ a device that combines a blood sugar monitor and an insulin pump to automatically give patients the dose of insulin that they need.

    These treatments aim to make up for the loss of beta cells. But a group of scientists has another solution: put the beta cells back in. The idea may sound too simple to be true, but it’s already yielded promising results and could free type 1 diabetics from having to inject insulin.  

    “What we would like to put back into diabetic patients is not just the hormone insulin, we would love to put back the beta cells,” said Matthias Hebrok, Ph.D., director of the UCSF Diabetes Center. “The beta cell is such a beautifully fine-tuned machine that it would … completely regulate sugar levels.”

    Beta cell transplants have already been done using cells from deceased organ donors. These cells grow in small clusters called islets, and over 1,500 diabetics have received islet transplantations.

    The procedure requires lifelong antirejection drugs to protect the transplanted beta cells, and is reserved for patients with unusually hard-to-treat cases of disease. But, thanks to improvements in the procedure, half of recipients remain off insulin five years after transplant.

    “These are people who cannot normally have a regular life … They cannot drive. If it’s a mom walking around with her kids — imagine [fainting] in the middle of the street. It’s really problematic. So an islet transplantation can really change their life,” said Maria Cristina Nostro, Ph.D., professor of physiology at the University of Toronto.

    But islet transplants wouldn’t work as a general therapy for type 1 diabetes. The issue boils down to basic supply and demand. Each year, organs from 7,000 donors are available in the US, but, in most cases, pancreatic islets — which are sensitive to stress and damage — cannot be salvaged. By comparison, up to three million Americans have type 1 diabetes. 

  • Using Embryonic Stem Cells

    So scientists are trying a different tack: forming beta cells from stem cells. Embryonic stem cells give rise to all the cells of the body, and researchers can make these cells become beta cells by controlling the genes they switch on and off. Large numbers of beta cells could be grown in a lab and then transplanted into a patient. In theory, stem cells would be an unlimited source of beta cells, as they can divide and replenish themselves.

    Because embryonic stem cells can grow into any cell type, one hurdle to overcome is the risk of forming unwanted, non-pancreas cells that could make cell-replacement therapy ineffective or unsafe.

    “You don’t want to transplant something that would give rise to a mini-gut at the same time as your potential pancreatic cell. You want to transplant into the patient something that is as close as possible to only pancreas,” said Dr. Nostro.

    To get purer populations of cells for transplant, Dr. Nostro and colleagues identified a surface protein made by cells fated to become pancreas cells. When grown in a dish, these cells can be coaxed to make insulin — a key property of beta cells. The findings were published in Nature Communications in August 2017. The group’s next step will be transferring these early pancreas cells into a mouse model of diabetes to test whether they stabilize blood sugar levels.

    A separate team of researchers at Denmark’s University of Copenhagen discovered the same protein earlier this summer. The project’s leader, assistant professor Jacqueline Ameri, Ph.D., now plans to form a spinout company known as PanCryos, which will be devoted to stem cell therapies for type 1 diabetes. Novo Nordisk, the world’s largest maker of diabetes drugs, is already supporting the work through its Novo Seeds fund for new biotech companies.

    Stem cells can generate enough beta cells for a transplant, but they can’t guarantee the survival of those cells. Type 1 diabetics are sick because their immune system destroyed their beta cells. Adding in more cells without protecting them from the immune system would be like grabbing a hot tray of cookies out the oven bare-handed — after you already were burned once before taking out the first batch.

    San Diego-based biotech company ViaCyte is working on that, and already has a couple clinical trials underway. In one Phase I/2 trial, cells that form all the cell types of the islet — including beta cells — are encased in membranes that allow small molecules like oxygen, glucose, and insulin to flow freely while blocking the transplanted cells from the recipient’s immune system. ViaCyte President and CEO Paul Laikind, Ph.D., compares the units to tea bags, which let water pass in and out but hold onto the leaves.

    Laikind believes ViaCyte’s therapies could one day be a “functional cure” for patients — stabilizing blood sugar levels without fixing the underlying autoimmune response. The company has received funding from numerous sources, including the California Institute for Regenerative Medicine and the Juvenile Diabetes Research Foundation.

    Cell replacement could also be used for some type 2 diabetes cases. Ninety to ninety-five percent of diabetics have type 2, in which beta cells make insulin but the body doesn’t respond to it. The cells react by churning out even more insulin, but can eventually wear out or die from the strain. UCSF’s Hebrok likens it to trying to sprint a marathon. Replacing beta cells could fit in with existing strategies to improve insulin response in type 2 diabetics, which mainly revolve around diet and exercise.

    Work in diabetes mirrors a broader shift towards cell-replacement therapies for other diseases, including macular degeneration and Parkinson’s, where there have already been promising early-stage human and animal trials. These cell-centered approaches will likely be buoyed by ongoing advances in stem cell biology and genetic engineering.

    And that’s something scientists are excited about.

    “This is an amazing period of time right now,” said Dr. Hebrok. “Science is just unbelievable, moving in ways, forms, and at a speed that is almost unprecedented.”

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