Approximately 1.25 million Americans are living with type 1 diabetes (T1D), with an additional 40,000 people newly diagnosed every year. T1D is an autoimmune disease that destroys insulin-producing pancreatic islet cells. Insulin is a hormone that allows sugar (glucose) to enter cells to produce energy. Without insulin, blood sugar accumulates, causing toxic side effects. Despite active research, T1D has no cure. While treatments, including daily insulin injections, are available, managing the disease remains challenging, and poorly controlled T1D can lead to blindness, organ failure and other health issues.
Replacement therapies for beta cells (the cells that produce insulin in the islet) have been proposed as a game changer for T1D patients, potentially freeing diabetics from the daily burden of constantly managing their disease. There are two main challenges to transplanting insulin-producing islet cells: the shortage of transplantable cells and the underlying autoimmune response that destroyed the patient's own islets.
Ronald Evans, a professor in Salk's Gene Expression Laboratory and a Howard Hughes Medical Institute Investigator, believes that the development of immune tolerant human islet-like organoids, or HILOs for short, may be a solution. He's not alone. The California Institute for Regenerative Medicine (CIRM) recently approved a $1.6 million grant to help bring Evans' HILOs to patients with diabetes.
"We are excited that CIRM has elected to support our work," says Evans. "Transplanted islet cells have the potential to dramatically improve the quality of life for people with type 1 diabetes, but we need to overcome the shortage of transplantable cells, and we need to manage the autoimmune response. We believe HILOs will do both."
HILOs build upon a breakthrough Cell Metabolism paper published in 2016, which identified the secret switch (ERR gamma;) to generating mature functional islet cells; that is, cells that secrete insulin when they sense high sugar levels. HILOs are generated from pluripotent stem cells (which have the potential to become any tissue) and can be grown in large numbers, potentially solving the transplant shortage. These organoids contain a variety of cells, as well as a blood supply, to recapitulate normal islet cell function. In addition, early animal studies have shown HILOs are highly functional, secreting insulin in response to glucose.
"Our engineered functional human islet-like organoids are designed to circumvent the shortage of donor islets," says Salk Research Associate Zong Wei, a member of the HILO project team. Salk Staff Scientist Eiji Yoshihara, a leading member of the HILO project team, notes, "In preclinical testing, our HILOs can immediately restore glucose homeostasis (balance) upon transplantation into T1D mice."
The project was funded under CIRM's Discovery Quest Program, which invests in research that can be rapidly translated into treatments. The team will use these funds to develop a safe and efficient protocol to scale up HILO production to eliminate islet cell shortages. From a therapeutic perspective, HILOs could provide the complete package: easily transplantable organoids that produce insulin, resist immune attack and can be grown in sufficient numbers.
"In addition to developing safe effective HILOs, we now have a way of cloaking the cells from the immune system, and thereby avoiding the autoimmune response that could destroy the implanted cells," says Senior Staff Scientist Michael Downes, a senior member of the HILO team. "This is an exciting time. Although it is early days, the funding from CIRM will help develop HILOs to improve the quality of patient lives."
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