Objective
Previously research demonstrated the potential for pancreatic islets coated around a blood vessel to restore blood sugar control in diabetic rats, which we have termed a “Biovascular Pancreas.” In order to make a larger version of this graft suitable for use in humans, we plan to coat the outside of a bioengineered tubular (6mm outer diameter) “Human Acellular Vessel” (HAV) with a gelatinous hydrogel containing living islet cells. Our first objective is to maximize the function and survival of the islet cells within this hydrogel coating both in a laboratory setting and in living organisms. In parallel, we will pursue our second objective to test the Biovascular Pancreas (BVP) in a non-human primate model to study the survival of the cells within the graft and their ability to respond and regulate elevated blood sugar levels. These objectives will help optimize the design, implantation, and monitoring of the Biovascular Pancreas as well as provide data that may enable the first human clinical trials of this novel therapy.
Background Rationale
Some patients with type 1 diabetes have significant challenges in controlling their blood sugar levels even with external insulin supplementation. These individuals face medical complications from poor control of blood sugar levels that can swing rapidly from hyperglycemia to hypoglycemia. For these individuals, the most appropriate therapy is a pancreas transplant or transplantation of insulin-secreting pancreatic cells (islets) retrieved from donor tissue to supplant those in the host damaged due to type 1 diabetes. Supplementation of new islets, however, requires an organ donation, isolation of fragile pancreatic islets, injection of these islets into veins in the liver, and then adherence to a life-long regimen of immunosuppressive drugs. While this technique works for some individuals, islets are cell clusters that require substantial nutrition from the blood vessels that flow around them in the pancreas. Isolation of islets from a donor organ removes them from this arterial blood vessel network which has higher oxygen levels than the venous blood they are then injected into upon transplantation. Therefore, many of the islets injected into the liver die because of inflammation and poor availability of oxygen and other essential nutrients. If too many islets die, then the surviving islets will be unable to generate enough insulin to support normal blood sugar levels. To better treat these patients, it is important to promote the survival of transplanted islets to maximize the chance of improving long-term control of blood glucose levels. Humacyte’s Biovascular Pancreas (BVP) would accomplish this by placing islets around the outside of a bioengineered tubular blood vessel, called a Human Acellular Vessel (HAV), that once implanted into the patient’s own circulatory system, would keep islets immediately adjacent to highly-oxygenated blood flow to maintain the health of these cell clusters. The HAV has an extensive track record of demonstrated safety with implantation into roughly 500 patients over the past ten years with no instances of clinical immune rejection, thereby providing a reliable vascular graft to support the Biovascular Pancreas. This research will also utilize islets derived from reprogrammed adult cells (induced pluripotent stem cells), which have enormous potential to be made into most other cell types in the body. By using these cells, the need for organ donation would be reduced or eliminated, allowing the BVP to be a readily-available therapy for patients with poor control of their blood sugar levels.
Description of Project
The loss of blood sugar control in type 1 diabetes can result in damage to many tissues in the body, especially the heart, blood vessels, nerves, kidneys, eyes, and extremities. These complications can be debilitating, and for patients who do not respond well to insulin supplementation, complications are more severe and new therapeutics are desperately needed. The pancreatic cells (called “islets”) damaged due to type 1 diabetes can be replaced by injecting donor islets into a patient, but efficacy of this procedure is limited, primarily due to death of the transplanted islets from lack of nutrient availability, especially oxygen, and inflammation. Previous research identified a potential solution to this problem: placing islets with a gelatinous “hydrogel” on the outside of a tubular, bioengineered vascular graft and then implanting this graft within the patient’s blood vessel network. This novel treatment, named a “Biovascular Pancreas” has so far shown success in preliminary studies using diabetic rats. Over the course of 90 days, the islets on the graft survived and the graft developed its own blood vessels through it, which help supply oxygen and nutrients to the islets. The islets secreted insulin that normalized blood sugar levels and could respond to dynamic changes in blood sugar. These results support further development of this concept, and in the proposed research, continued work on the islet cell source and hydrogel coating for the vessel will identify the conditions that best support islet survival and function in larger animal studies in order to provide vital data that hopefully leads to the evaluation of the Biovascular Pancreas in human clinical trials and a novel treatment for those suffering from type 1 diabetes.
Anticipated Outcome
Our initial experiments showed the potential for the Biovascular Pancreas (BVP) to restore normal blood glucose levels in diabetic rats. However, studies in larger animals are necessary to optimize and evaluate this potential therapy for type 1 diabetes before initiating human clinical trials. The studies proposed in this grant will determine the best methods for making the coating of the BVP and the best conditions for supporting the survival and function of the islets contained within the graft. We expect that a hydrogel coating comprised of fibrin, an abundant protein found in the blood, will be able to be secured to the outside of the acellular vascular graft and support the survival of islets outside of a patient to allow enough time to both make the therapeutic graft and transport it to a hospital site for implantation into a patient. Once implanted as a BVP graft, we expect the fibrin hydrogel to provide a stable coating that will contain the islets near the luminal blood flow, permitting transport of vital oxygen and nutrients to keep the islets alive until the host’s cells establish a capillary network through and around the BVP to support survival and enhance function of the implanted islets. Based on our earlier work in rats, we expect that a primate version of the Biovascular Pancreas using primate islets will be able to reduce the blood sugar levels of diabetic primates and reestablish normal blood sugar levels in response to spikes in blood sugar. We expect these data together then would inform either further primate studies or the basis for approval for a human clinical trial.
Relevance to T1D
Patients with type 1 diabetes, particularly those with “brittle” type 1 diabetes and poor control of their blood sugar, have limited therapeutic options. Transplantation of islets from an organ donor can provide control of blood sugar for some patients, but efficacy of this therapy is limited. This proposed research project looks to generate a potential cure for type 1 diabetes by administering a therapeutic number of islets to diabetic patients and optimizing the function of these cells by placing them securely on a non-immunogenic, acellular vascular graft connected to the patient’s own blood vessels. This would provide an ideal environment for the islets to survive and secrete insulin to naturally regulate blood glucose levels and thereby cure type 1 diabetes.