Objective
The objective of this proposal is to overcome the current clinical hurdles facing islet transplantation while streamlining clinical translation, by integrating three validated islet graft-localized therapeutic delivery systems to enhance islet survival and function when transplanted under the skin: System 1 - Grattoni’s subcutaneous NICHE implant will be used as a device to host the transplanted islets while providing sustained local delivery of immunomodulatory molecules to abrogate graft rejection. System 2 - Korbutt and Pepper’s biodegradable scaffolds will be used within the NICHE cell reservoir to achieve optimal site blood vessel formation, without the need for accessory cells, which may represent a regulatory barrier. System 3 - Finally, we will integrate Korbutt and Pepper’s localized drug-delivery microparticles, to temporarily supply the microenvironment with stress islet inhibitors to support islets during the early phase of engraftment.
Background Rationale
One obstacle for successful clinical islet cell transplantation is the poor survival of the islets in the immediate post-transplant period. The cause of this is largely due to a poor supply of blood vessels in the transplant site. The objective of this proposal is to overcome the current clinical hurdles facing islet transplantation while streamlining clinical translation, by integrating three validated islet graft-localized therapeutic delivery systems to enhance islet survival and function when transplanted under the skin. We hypothesize that tethering these proven transplant platforms will allow us to create a highly translational product permitting long-term islet graft function without systemic immunosuppression.
Description of Project
The objective of this proposal is to overcome the current clinical hurdles facing islet transplantation while streamlining clinical translation, by integrating three validated islet graft-localized therapeutic delivery systems to enhance islet survival and function when transplanted under the skin: System 1 - Grattoni’s subcutaneous NICHE implant will be used as a device to host the transplanted islets while providing sustained local delivery of immunomodulatory molecules to abrogate graft rejection. System 2 - Korbutt and Pepper’s biodegradable scaffolds will be used within the NICHE cell reservoir to achieve optimal site blood vessel formation, without the need for accessory cells, which may represent a regulatory barrier. System 3 - Finally, we will integrate Korbutt and Pepper’s localized drug-delivery microparticles, to temporarily supply the microenvironment with stress islet inhibitors to support islets during the early phase of engraftment.
We hypothesize that tethering these proven transplant platforms will allow us to create a highly translational product permitting long-term islet graft function without systemic immunosuppression.
To test this hypothesis, we propose 3 experimental aims that will assess the translational potential of our refined and synergized localized islet graft product, in the span of 3 years:
Aim 1. Eliminate the need for mesenchymal stem cells (MSC) for NICHE vascularization. Aim 1.1. Examine the kinetics of NICHE blood vessel formation using functionalized scaffolds as compared to MSC prevascularization, in rats. Aim 1.2. Evaluate the safety and efficacy of syngeneic rat islet grafts transplanted into prevascularized NICHE (using optimal conditions from Aim 1.1) in conjunction with or without drug-eluting microparticles targeting inflammation, insulin secretion and cell death responses (e.g. apoptosis, regulated necrosis) to mitigate islet stress. This aim will aid in defining the optimal prevascularization strategy for islet allografts transplanted into the NICHE.
Aim 2. Optimize islet allograft survival transplanted into the subcutaneous NICHE. Based on the findings from Aim 1, we will evaluate the survival of rat islet allografts transplanted into the NICHE by exploiting its reloadable reservoir for controlled, sustained release of CTLA4Ig and thymoglobulin. The study will be conducted with or without islet co-transplantation with PLGA MPs delivering the optimal combination of tropic factors (established in Aim 1.2).
Aim 3. Translational studies and scale-up. We will scale and define the efficacy of our refined and integrated transplant product (Aim 2) in a series of pilot clinically relevant large animal studies. Aim 3.1. Evaluate neonatal porcine islet allograft survival transplanted as sentinel grafts in non-diabetic pigs. Aim 3.2. Develop clinical grade manufacturing protocols and regulatory strategies to bring this product to the clinic to treat patients with type 1 diabetes.
Anticipated Outcome
We anticipate that our novel approach using our collaborative three validated islet graft-localized therapeutic delivery systems will lead to long-term durable islet graft function as well as circumvent the complications associated with systemic immunosuppression.
Relevance to T1D
We hypothesize that our collaborative three validated islet graft-localized therapeutic delivery systems will lead to long-term islet graft function and thereby broaden the spectrum of T1D patients eligible to receive a curative islet cell replacement therapies.