Objective
To develop clinically translatable platform for localized immunomodulation based on dose controlled and feedback regulated anti inflammatory cytokine delivery platforms. This platform can be used in combination with any form islet grafts to locally suppress immune responses to facilitate improved viability and survival of transplanted islet grafts. Our goal to further build upon the advancements of encapsulated islet therapies and develop combination products that can be co administered with islet grafts to achieve even longer and improved function post transplantation
Background Rationale
Cytokine-based immunotherapy is a promising solution for improving transplanted islet graft survival and viability, but many of these therapies are toxic at therapeutic doses and thus elicit detrimental off-target effects for patients. To address the need to deliver anti inflammatory cytokines adjacent to transplanted grants to locally modulate host immune responses without significantly increasing the cytokine concentration in systemic circulation, the PIs propose the design of a series of cell-based, sense-and-respond platforms that continuously deliver cytokines into the islet transplant microenvironment with tunable dosage and therapeutic window duration
Description of Project
General Audience Summary
Type I Diabetes (T1D) is an autoimmune disorder that affects 1.25 million American today, and recent epidemiological studies suggest that T1D incidence is rising. Despite decades of research the current standard of care for those suffering from type I diabetes (TID) remains a rigorous regimen of blood glucose monitoring together with daily administrations of exogenous insulin and diabetic diet, these individuals still are challenged with untoward side effects due to complications of the disease in part the result of daily compliance issues. Islet transplantation has tremendous potential, but serious technological limitations remain. While there has been significant progress made in developing cell encapsulation biomaterials with improve biocompatibility the cytokine cascade associated with the host immune responses to transplanted encapsulated cellular constructs remains a major a major contributing factor to poor islet viability and function. Immunomodulation strategies through localized cytokine therapy can significantly improve islet viability and survival, but serious technological limitations remain. Intravenous administration of inherently recombinant cytokines with reduced stability and bioactivity requires high/frequent doses that cause severe side-effects forcing patients to stop treatments. New drug delivery platforms that provide spatial and temporal control of cytokine delivery can significantly improve localized immunotherapy outcomes and reduce toxicities.
To address this challenge, we propose to develop a programmable drug delivery platform that consists of immunomodulatory hydrogels encapsulating cells engineered to produce the anti-inflammatory cytokines. Our cell-produced cytokines are more potent and bioactive than their recombinant counterparts. Encapsulated islet graft adjacent implantation of these cytokine factories allows for continuous local delivery of natural cytokines while limiting systemic exposure and associated side effects. To develop this platform, we leverage modified alginate analogs that allow long-term treatment regimens. To ensure safety and robustness of the developed platform, cells are further engineered with sense and respond capabilities to control dosage and the duration of therapy.
Upon completion of this project, three clinically translatable platforms for regulated delivery of cytokines delivery to localized compartments within the body for improved viability and survival of encapsulated islets. Each platform is developed to produce therapy with different target product profiles. The first one enables on-demand termination of treatment through small molecule activation. The second one is engineered to enable tunable therapy windows based on the biomarker of treatment efficacy. The third platform is engineered to compensate for patient-to-patient heterogenicity through a feedback-regulated mechanism to control cytokine production rate. These tools could be used independently or in combination with one another to facilitate safer and more effective localized immunomodulation to improve encapsulated islet therapy. Moreover, the platform is generalizable and can be adapted to produce other immunomodulatory molecules for a wide range of clinical applications.
Anticipated Outcome
Upon completion of this project, three clinically translatable platforms for regulated delivery of cytokine delivery to the peritoneal space for local immunomodulation for islet graft survival and viability will be developed and validated in mouse studies. Each platform is developed to produce therapy with different target product profiles. The first one enables on-demand termination of treatment through small molecule activation. The second one is engineered to enable tunable therapy windows based on the biomarker of treatment efficacy addressing the needs based on inflammation flareups. The third platform is engineered to compensate for patient-to-patient heterogenicity through a feedback-regulated mechanism to control cytokine production rate. These tools could be used independently or in combination with one another to facilitate safer and more effective cytokine therapy for improving islet graft viability and survival. Moreover, the platform is generalizable and can be adapted to produce other immunomodulatory molecules for a wide range of clinical applications
Relevance to T1D
Diabetes remains a global epidemic afflicting more than 300 million people worldwide, with incidence only expected to rise. Despite decades of research the current standard of care for those suffering from type I diabetes (TID) remains a rigorous regimen of blood glucose monitoring together with daily administrations of exogenous insulin and diabetic diet, these individuals still are challenged with untoward side effects due to complications of the disease in part the result of daily compliance issues. Islet transplantation has tremendous potential, but serious technological limitations remain.A fundamental challenge to successful islet transplantation is host immune responses to transplanted islet grafts. Here we propose a localized immunomodulating strategy to address this limitation. Our proposed cytokine factories can be used with any form of islet graft transplants to reduce host mediated inflammation that contributes to poor viability and function of transplanted pancreatic islets.