Objective
To determine the minimum amount of stem cell-derived insulin-producing β cells needed to control blood glucose when delivered under the skin on a biomimetic scaffold, and to measure how the body responds to that scaffold in a clinically relevant large-animal model, generating key data needed to plan first-in-human studies for Type 1 Diabetes.
Background Rationale
Type 1 diabetes, which affects an estimated 3 million Americans, is caused by immune destruction of insulin-producing β cells, leading to the need for lifelong insulin therapy. Over time, serious complications can develop, including retinopathy, neuropathy, kidney disease, stroke, and heart disease. Although insulin injections are effective, hypoglycemic episodes and long-term vascular complications can still occur. For this reason, recent research has focused on stem cell–based therapies that aim to generate and replace lost insulin-producing cells.
Replacing β cells could restore the body’s ability to regulate blood glucose, but achieving long-term survival and function of transplanted cells remains challenging. The subcutaneous space (under the skin) is attractive because it is accessible, can be monitored, and may allow retrieval if needed; however, it often provides limited oxygen delivery and can trigger a strong foreign body response that leads to fibrotic encapsulation and loss of function.
We developed a biomimetic scaffold designed to provide reproducible native-like microarchitecture for these cells and improves access to nutrient and oxygen, similar to that in the pancreas. The scaffold helps organize stem cell-derived beta cell clusters and support their long-term survival and function in the subcutaneous space after transplantation. Preliminary studies in immunodeficient mice support the feasibility of this approach. Preliminary studies in immunodeficient mice support the feasibility of this approach. The next step is to generate IND-aligned nonclinical data by defining dose requirements in a diabetic small-animal model and quantifying the host response to the scaffold in a large-animal model, while advancing manufacturing and testing methods needed for FDA regulatory readiness and to de-risk first-in-human studies.
Description of Project
Type 1 diabetes occurs when the immune system destroys the body’s insulin-producing β cells, leading to the need for lifelong insulin therapy. Over time, serious complications can develop, including retinopathy, neuropathy, kidney disease, stroke, and heart disease. Although insulin injections are effective, hypoglycemic episodes and long-term vascular complications can still occur. For this reason, recent research has focused on stem cell-based therapies that aim to manufacture and replace lost insulin-producing cells.
Replacing insulin-producing β cells made from human stem cells could restore the body’s ability to control blood glucose, but long-term survival and function of transplanted cells remain difficult. A major challenge is selecting a safe and practical transplant site that also supports these cells. The subcutaneous space (under the skin) is attractive because it is accessible, can be monitored, and may allow retrieval if needed. However, it often provides poor oxygen and nutrient delivery and can trigger a strong foreign body response, which may lead to scarring around implants and loss of cell function.
Our team has developed a biomimetic scaffold designed to support stem cell-derived β cell clusters (sc-β) in the subcutaneous space. This scaffold is engineered to provide a reproducible microarchitecture that creates a more native-like environment for these cells, similar to that in the pancreas and further improving their access to oxygen and nutrients. In preliminary studies in immunodeficient mice, we showed that the scaffold supported sc-β maturation, persistent survival and improved function over long durations. Building on this foundation, the proposed project will evaluate clinically relevant cell sources on the scaffold and generate the dose, safety, and host response data needed to support an FDA pre-IND discussion and, ultimately, first-in-human studies.
Anticipated Outcome
This project is expected to produce three practical outcomes. First, it will identify the minimum dose of stem cell-derived insulin-producing cells that can reliably improve glycemic control when delivered subcutaneously using our scaffold in a standard preclinical diabetes model. Second, it will characterize the host response to the scaffold in a large-animal model that more closely reflects human tissue responses, including whether the implant becomes surrounded by excessive fibrotic tissue or instead maintains a healthier, better-perfused environment. Third, it will establish standardized methods to manufacture and test the combined cell-and-scaffold product so results can be compared across studies and used to plan the next set of required safety evaluations. Together, these outcomes will determine whether this approach is ready to advance to FDA regulatory discussions and support planning for a first-in-human clinical program.
Relevance to T1D
People with Type 1 diabetes must manage blood glucose every day with insulin, and even with modern devices, severe hypoglycemic events and long-term complications affecting the eyes, kidneys, nerves, and heart can still occur. A β-cell replacement therapy that restores the body’s own insulin production could reduce these risks and improve quality of life, but progress has been limited by the challenge of keeping transplanted cells alive and functional over the long term, especially in transplant sites that are safe and practical for patients.
If successful, this work will advance a β-cell replacement approach delivered under the skin that is designed to be minimally invasive, monitorable, and potentially retrievable. These features are important for patient safety and real-world clinical use. By defining the cell dose needed for durable glycemic control and quantifying the host response to the scaffold in a large-animal model, this project addresses key barriers that have historically limited the clinical success of β-cell replacement therapies. These results are intended to accelerate the path toward a therapy that could reduce or eliminate the need for insulin injections and improve long-term outcomes for people living with Type 1 diabetes.