Objective
There is considerable promise in islet transplantation therapy to cure type 1 diabetes (T1D). As more favorable immunosuppressive therapies are being developed, a significant challenge to effective islet transplantation remains scaling to larger islet grafts needed for patients while preserving islet health. Our goal is to advance a proven prevascularized islet graft solution beyond the small animal stage by fabricating a larger, validated version of the vascularized islet graft intended for implantation. Importantly, the design is flexible, accommodating a variety of beta cell sources, vascularization and support cells, and matrices. Additionally, we will implement a manufacturing process that enables scalable graft production in numbers and size, thereby meeting clinical needs.
Background Rationale
Considerable efforts by the scientific and medical communities are focused on developing cures for type I diabetes. One very promising approach involves the transplantation of donor islets or engineered beta cells into T1D patients, eliminating the need to use insulin injections to control blood sugar (called insulin independence). Research shows that transplanting small volumes of islets or beta cells as grafts under the skin of mice can establish normal blood sugar levels long term. However, unlike in these mouse studies using small islet grafts, the islets (or beta cells) of the large grafts needed to cure patients become starved for oxygen and nutrients because they are too far away from the surrounding blood supply of the skin. The inability to keep islets alive in these larger grafts is a significant challenge and is limiting the full promise of islet transplant therapy in patients. Building vessels within the islet grafts (called prevascularization) can help improve graft viability/persistence after transplantation. Indeed, we have developed an effective prevascularization strategy for this purpose. Yet, this solution needs to be transformed into a larger version in order to be useful for patients. Additionally, larger grafts are harder to build, limiting the number of patients that can be treated at a time. We propose a large, prevascularized islet graft solution based on the successful small, prevascularized graft mentioned above, but redesigned to keep transplanted islets close to a blood supply at all times and further support islet health once transplanted. Furthermore, the graft design is readily made, using advanced robotic bioprinting, and is compatible with scaled biomanufacturing.
Description of Project
Islet transplantation and related beta cell replacement therapies can establish insulin independence for patients with type 1 diabetes (T1D) and intractable high blood sugar. However, 50-75% of these patients lose the benefit of the transplanted islets after 5 years, requiring insulin injections. A significant amount of islet loss after being transplanted happens, in part, because islets are usually transplanted into the liver blood stream, which is not an ideal environment for islets. Consequently, a variety of sites outside of the liver are being considered, including under the skin. Research is showing that transplantation of prevascularized (i.e., contains premade capillaries) islet grafts under the skin of mice can be very effective and offers considerable promise for treating T1D. However, larger versions of these small grafts containing more islets are needed to effectively treat patients. However, making larger islet grafts that remain viable and functional when transplanted remains a significant hurdle. To solve this, we are developing a unique large, prevascularized islet graft for use in treating T1D patients. Importantly, the graft design is based on the effective small grafts used in mice but redesigned to work as a larger graft for use in patients. The project involves building these large, prevascularized, islet grafts using advanced robotic bioprinting and proving that the grafts functions normally when implanted. Furthermore, we will develop the biomanufacturing process capable of making enough of the large, prevascularized grafts to treat the approximately 1.8 million type I diabetics in the US and nearly 9 million T1D patients worldwide.
Anticipated Outcome
Through the efforts of our very capable team, we are developing a manufactured, scalable islet graft solution for the treatment of T1D in patients. The graft is based on a proven strategy and uniquely designed to promote islet (or beta cell) health within large grafts transplanted under the skin. Furthermore, we will test the ability of the large graft to establish normal blood glucose levels in a diabetic rat. Importantly, to realize the full utility in treating large numbers of T1D patients, we will establish a biomanufacturing process that enables the scaled production of the large graft. With completion of the project, the large islet graft solution will be positioned to begin the necessary preclinical and regulatory studies preceding the treatment of patients.
Relevance to T1D
The mission of Breakthrough T1D is accelerating life-changing breakthroughs to cure, prevent and treat T1D and its complications. It’s estimated that there are over 1.8 million type I diabetics in the US and nearly 9 million T1D patients worldwide. These patients must use daily injections of insulin to replace the action of the pancreatic islets, which normally produce insulin and balance blood sugar. Our proposed solution, an islet transplant therapy, is intended to replace T1D patients absent islet activity, managing blood sugar levels without the need for insulin injections. Our focus in the project is to address a significant hurdle in islet transplantation which is the manufacturing of a large, prevascularized islet graft that stays healthy and active when transplanted. In this way, we offer a strategy that could benefit a large number of T1D patients.