Objective
To accelerate the widespread availability of insulin producing beta (β)–cell replacement therapies for the treatment of type 1 diabetes (T1D), the proposed work will generate key efficacy and safety data that will generate a regulatory package leading to approval by the US FDA for a clinical proof of concept study using human islets contained within oxygen-enabled, retrievable, high-capacity, small footprint non-immunoisolating devices. Establishing key parameters, providing pre-clinical data, and adhering to regulatory agency stipulations will allow for the fast-tracked use of this technology for clinical application and eventually the use of ‘stealth’ stem cell derived islets without the need for immunosuppression when such cells become available. Ultimately, this technology will maintain long term β-cell viability and function through enhanced oxygenation in an ‘open’ device that allows for blood vessel formation (vascularization) within the device and within cells in the device. This will ensure that encapsulated β-cell replacement has superior outcomes compared to standard islet transplantation and is available to a greater number of T1D patients using a retrievable device approximately half the size of a credit card implanted under the skin.
Background Rationale
The large-scale implementation of insulin producing beta (β)-cell replacement therapies as the standard of care for patients suffering with type 1 diabetes (T1D) is currently limited by insufficient human islet availability, the requirement for lifelong and potentially harmful systemic immunosuppression in transplant recipients, and by inefficiencies of the transplant sites, including a low supply of oxygen to engrafted islets (hypoxia). A significant amount of transplanted islets in the traditional liver (hepatic) portal vein site die shortly post-transplant due to oxygen starvation prior to re-vascularization. Given the limitations of islet transplantation and the inability to retrieve the transplanted cells from this site if necessary, substantial efforts are directed towards the development of encapsulation technologies which better support transplanted cells and allow for cell retrieval.
Retrievable, macro-encapsulation devices containing insulin producing β-cells that can be transplanted in alternative sites (for example subcutaneously - under the skin) are attractive in this regard. Macro-encapsulation devices have been extensively tested in small and large animal models as well as in humans; however, there is increasing consensus and emerging data from clinical testing, supporting predictions based on mathematical modelling that that the efficacy of encapsulation approaches for the treatment of diabetes (with or without immunoisolation) is compromised by hypoxia when scaled for human use, Both the low oxygen level at transplant sites and the potential requirement of an immunoisolation barrier in the device, which prohibits the formation of blood vessels within the device and protects cells within the device, restrict the number of insulin producing β-cells that can be loaded per device without sacrificing β-cell viability and function. This results in unacceptably large human-sized devices. In contrast, since autologous, stealth allogeneic (e.g. human “stealth” stem cell derived islets, a source with potentially unlimited supply), or allogeneic transplants under the coverage of immunosuppression do not require an immunoisolation barrier, device and cell vascularization can be permitted, which eliminates the need for permanent oxygen supplementation; islets need only be provided with sufficient oxygen to survive during the re-vascularization period (estimated to be around 4-6 weeks). In this case, oxygen delivery can be permanently terminated once sufficient blood vessel growth within the device is accomplished. This approach can potentially enable reversal of T1D in humans with a device less than half the size of a credit card without the need for immunosuppression.
Description of Project
The transplantation of insulin producing beta (β)-cells is a proven treatment of Type 1 Diabetes (T1D) but cannot be widely applied to treat the millions of people in need because of two critical limitations: the shortage of human pancreas donors from which islets are isolated, and the subsequent requirement for lifelong immunosuppression, which can be both costly and potentially life-threatening. The problem of β-cell shortage can be partially circumvented by improving transplanted β-cell function – thus conserving cells - by using an oxygenated encapsulation device that reduces the overall device size yet maintains cell viability and potency. Eventually, however, the use of a virtually unlimited source of immune-evading “stealth” β-cells derived from stem cells will ensure that cellular therapies are clinically acceptable, affordable, and accessible to all T1D patients.
Encapsulated cellular transplants are less invasive and less expensive than the standard procedure of islet transplantation into the liver. Conceptually, cellular therapy is more convenient and efficacious than insulin pumps because transplanted cells retain their ability to continuously monitor blood glucose and immediately respond to changes in its level, just like the normal pancreas. However, to use such cells, they must be placed in a retrievable device to address safety concerns, and the device must be of acceptable size. These considerations create the need to provide temporary, supplemental oxygen to the device to order to maintain cell function. If the device is equipped with an immunoisolation membrane to protect the transplanted cells from the immune system, thus negating the need for lifelong systemic immunosuppression, the device will likely require a long-term oxygen supply to support the cells within a device of reasonable size.
Patients who are already receiving immunosuppression (for example, previous recipients of a kidney transplant to treat renal disease, a common comorbidity of T1D) would be potential candidates for devices without an immunoisolation barrier. However, packing β-cells in such devices at a density that allows shrinking the devices to the size of half a credit card, instead of a large flat TV screen(!), starves the cells of oxygen, suffocating them. Providing the β-cells with extra oxygen until sufficient blood vessel formation within the devices is achieved - the focus of our proposal - is critical to the success of this approach. Eventually, using alternative sources of β-cells (such as stem cells modified to immunologically match the recipient or to “hide” them from the host’s immune system) and optimizing long term β-cell health and function through temporarily enhanced oxygenation in non immunoisolating devices will ensure that this treatment has superior outcomes to standard islet transplantation, is cost-effective, and is available to far greater numbers of T1D patients.
In order to facilitate the widespread availability of β-cell replacement therapies for the treatment of T1D, the proposed study will provide the pre-clinical data required by regulatory agencies to approve clinical investigations of human islets contained within retrievable devices temporarily supplied with oxygen from an external source.
Anticipated Outcome
This project will be guided by two specific aims. First, to demonstrate diabetes reversal using human islets in diabetic rats, cells are tightly packed in non-immunoisolating devices with an external oxygen delivery source. Then, once blood vessels are established within the device, oxygen delivery is terminated, after which maintenance of a non-diabetic status (normoglycemia) is demonstrated. Second, to conduct investigational new drug (IND)-enabling studies (required by the FDA) in diabetic rats, to confirm the long-term sustainability of a curative dose of human islets within non-immunoisolating clinical-grade devices at a high density (when translated to a human, a size roughly less than half of a credit card) and to establish surgical techniques and useability studies pertaining to the devices.
To complete these specific aims, we have formed a team of experts in the field of clinical islet isolation and transplant, stem cell and diabetes therapy, oxygen delivery, device and cell regulatory aspects, and device development and manufacturing.
Relevance to T1D
Type 1 diabetes (T1D) is a lifelong metabolic disorder that demands viable treatment options. Insulin producing beta (β)-cell replacement is a practical approach to the treatment of T1D but cannot be implemented to treat the millions of people in need due to human donated organ shortages and the need for lifelong immunosuppression. A partial solution to the problem of islet shortage is the more efficient use of the available precious resource of human islet β-cells; this will ensure that cell therapies are more affordable and more accessible to T1D patients. Encapsulated β-cell therapy is less invasive and less expensive than islet transplantation in the liver. It is more efficacious and convenient than insulin pumps due to the cells’ ability to monitor blood glucose and respond to that glucose level.
Ultimately, this project will allow for a quicker and more efficient clinical translation of encapsulated cell therapy for the treatment of type 1 diabetes using fewer cells by maintaining encapsulated cell viability and function by providing oxygen until blood vessel formation can be achieved. This also allows reducing the size of the device to roughly half the size of a credit card. Eventually, this technology can eliminate the need for immunosuppression by using immune-evading “stealth cells”, which would provide an unlimited source of insulin producing cells.