Objective
My research proposal encompasses the development of an innovative local drug delivery technology with the dual purpose of targeting both innate and adaptive immune reactions to protect transplanted islets. The primary objective is to achieve efficient transplantation without the need for lifelong immunosuppression, thereby mitigating the side effects associated with systemic immunosuppression. Through the optimization of co-transplantation of islets and local drug delivery systems, as well as the implementation of local immunomodulation techniques to create an immune cloak at the transplantation site, the goal is to provide robust protection for transplanted islets and ensure their long-term functionality, ultimately leading to the cure of diabetes.
Additionally, my research investigates the effects of immunomodulators on immune responses, aiming to enhance transplantation protocols by fine-tuning the immune environment. By gaining a comprehensive understanding of how immunomodulators influence immune reactions, we can refine and optimize the transplantation process to improve outcomes. This research will shed light on the intricate mechanisms underlying immune responses to transplanted islets and guide the development of more effective therapeutic strategies.
Overall, objective of my research is to significantly improve the feasibility and success of islet replacement therapy, paving the way for its broader availability and offering an improved quality of life for individuals living with type 1 diabetes. By developing novel drug delivery technologies and elucidating the complex interactions between immune cells and transplanted islets, we can overcome the limitations of current approaches and move closer to achieving a cure for this chronic condition.
Background Rationale
Beta cell replacement therapy holds promise for restoring normal glucose homeostasis in individuals with type 1 diabetes through the transplantation of beta cells. However, the widespread application of islet transplantation is hindered by limitations such as limited availability of donor islet tissue and the need for lifelong immunosuppression. These challenges are exacerbated by the proinflammatory immune reaction post-transplantation, which increases graft immunogenicity and compromises the functionality of surviving beta cells. Additionally, the heightened inflammatory response of pancreatic islets necessitates potent immunosuppression, further compromising the protective immune response.
This study aims to overcome these hurdles by engineering miniature implantable drug depots capable of protecting and ensuring islet survival through the modulation of innate and adaptive immune system at the islet graft site, thereby eliminating the need for systemic immunosuppression. The hypothesis is that short-term local suppression of effectors for innate and adaptive immune system, combined with immune regulation, will provide long-term protection for islets.
As a postdoctoral scholar in the Department of Bioengineering and Diabetes Center, I have actively been involved in developing biomaterial and drug delivery platforms for long-term beta cell survival and immune protection. I have successfully developed an immune-protective islet macroencapsulation device that is prevascularized and replenishable. Our results have recently been published. Additionally, I have designed and utilized injectable and implantable drug delivery platforms to deliver anti-VEGF and tobramycin for managing chronic diseases such as age-related macular degeneration and cystic fibrosis, respectively. The findings of these studies have also been published in journals. Moreover, I have successfully employed implantable microdevices loaded with decorin and βNGF for heart and bone tissue regeneration.
Therefore, I have extensive experience in developing local and targeted drug delivery technologies. Coupled with successful work in tissue regeneration and biomaterial engineering for islet immune protection, prevascularization, and long-term survival, I am well equipped to undertake the development of drug delivery technology for innate and adaptive immune system targeting local delivery of immunomodulators to enable systemic immunosuppression-free efficient islet transplantation.
Considering that transplantation of free islets or even encapsulated islets of allogeneic or xenogenic origin could trigger an immune response due to cytokine release and neo cell surface antigens, the successful implementation of our proposed local immune modulation strategies using targeted local delivery of immune modulators by cotransplanting them with islets at the graft site has the potential to simultaneously block the innate and adaptive immune system. Thus the ability to protect the islet graft resulting into immunosuppression free long-term efficient of islet transplantation. This strategy will help expand access to beta cell replacement therapy for a larger population of type 1 diabetic patients.
Description of Project
The current standard of care for individuals with type 1 diabetes (T1D) involves regular insulin injections, providing temporary relief but with lifelong limitations. While various therapies are being explored for autoimmunity and beta-cell restoration, islet replacement therapy remains the only approach demonstrating clinical proof of concept for comprehensive glucose control and independence from exogenous insulin in long-standing T1D cases.
However, widespread implementation of islet replacement therapy faces challenges, primarily immune rejection of grafts, which poses a significant barrier to successful islet transplantation and limits the utility of allogenic and xenogenic islets. Allogenic islets are sourced from human donors, while xenogenic islets come from animals like pigs. After transplantation, these islets are recognized as foreign by the recipient's immune system, leading to their destruction and impaired function. As a result, recipients must undergo lifelong systemic immunosuppression to prevent rejection, which can have potential adverse effects and burdensome consequences for patients. Therefore, it is crucial to develop innovative strategies that enable efficient islet transplantation while preserving the integrity of the patient's immune system.
To address these challenges, my research focuses on the local delivery of immunomodulators as a potential solution to simultaneously target the innate and adaptive immune systems. The goal is to develop targeted delivery systems for immunomodulatory agents, creating a localized immunosuppressive environment at the transplantation site, thereby mitigating immune-mediated rejection and eliminating the need for systemic immunosuppression.
The research proposal consists of two primary aims:
1. Design and optimization of biomaterial-based drug delivery microdevices: This involves developing implantable microdevices capable of sustained and controlled release of immunomodulators to target the innate and adaptive immune reactions. Precise drug delivery aims to create a localized immunosuppressive environment at the transplantation site, promoting graft acceptance and long-term viability.
2. Investigation of immune microenvironment modulation: Comprehensive immunological assessments and characterization will be conducted to understand the impact of local immunomodulation on the immune microenvironment surrounding transplanted islets, along with the drug delivery microdevice. These findings will refine delivery strategies and optimize the transplantation process.
The research entails fabricating and characterizing a drug delivery microdevice, conducting in vitro characterization of drug release kinetics, utilizing diabetic animal models for allogenic/xenogeneic islet transplantation using the immunomodulatory microdevice, and employing extensive immune profiling techniques. This multidisciplinary approach aims to gather crucial data to evaluate the efficacy and safety of the localized immunomodulation approach. The research will provide valuable insights into the mechanisms by which immunomodulators influence immune cell behavior and promote an immunotolerant milieu, thereby preventing islet graft rejection.
The achievement of efficient islet transplantation without systemic immunosuppression holds immense promise. Enhancing the clinical feasibility and success rates of islet replacement therapy can preserve the overall immune function of T1D patients and broaden the availability and implementation of this curative approach, benefiting a larger population.
Considering the complexity of the immune system and the challenges in translating laboratory findings, contingency strategies include exploring alternative immunomodulatory agents, optimizing delivery platform design and release characteristics, and potentially combining immunomodulation with other immune tolerance induction strategies, such as using genetically modified immune-invisible islets.
In summary, the research proposal for the local delivery of immunomodulators to target the innate and adaptive immune systems presents a promising avenue for overcoming the limitations of current islet replacement therapy in treating T1D and achieving insulin independence.
Anticipated Outcome
As an expert in engineering biomaterials, drug delivery, and immunology, I am confident in my ability to achieve the aims of this study. At the end of the proposed research, I will have preclinically validated drug delivery technology for simultaneously targeting adaptive and innate immune system. The technology developed will include candidate targeting molecule and implantable local drug delivery device that will synergically block acute inflammation and subsequent immune cell activation responsible for killing the islet graft. Since the drug delivery technology I will develop modulate the an immune system locally it also alleviate the need for the systemic immune suppression. Through localized and targeted delivery of immunomodulatory agents, I will be able to create an immune-privileged environment around transplanted islets, protecting them from immune rejection and ensuring their sustained functionality.
The outcomes of my study would have a significant impact on the field by expanding the feasibility and success of allogenic and xenogenic islet replacement therapies. By eliminating the need for systemic immunosuppressive drugs, my approach would broaden the range of patients who can benefit from islet transplantation.
In conclusion, my expertise in biomaterials, drug delivery, immunology, and tissue engineering, coupled with the promising preliminary results, positions me well to demonstrate the efficacy and safety of the engineered drug delivery technology in preclinical T1D models. The success of this research would advance islet replacement therapy, benefiting a larger population of patients by offering them a long-term treatment option and the potential for a cure for T1D.
Relevance to T1D
My proposed research work, titled "Local Delivery of Immunomodulators to Enable Systemic Immunosuppression-Free Efficient Islet Transplantation," holds significant relevance to type 1 diabetes (T1D) and demonstrates both clinical importance and translational potential. In terms of clinical importance, my research aims to enhance islet transplantation for T1D by improving treatment efficacy, reducing treatment burdens, and potentially offering a cure. Through the development of innovative localized and innate and adaptive immune system targeting drug delivery technology to protects transplanted islets from immune rejection without the need for lifelong immunosuppression, my approach can improve the effectiveness of islet replacement therapy and alleviate the challenges associated with daily insulin injections.
The translational potential of my research is equally noteworthy. It has the potential to broaden patient access to islet replacement therapy by eliminating the requirement for lifelong immunosuppressive drugs. Additionally, through investigating the impact of immunomodulators on immune responses during islet transplantation, my research can optimize transplantation protocols and improve outcomes. Successful preclinical demonstrations of the efficacy and safety of the engineered drug delivery technology could pave the way for its translation into clinical practice, advancing the feasibility and adoption of islet replacement therapy as a mainstream treatment option for T1D.
In summary, my research is highly relevant to T1D and offers important clinical implications, including improved treatment outcomes, reduced treatment burdens, and the potential for a cure. Its translational potential lies in expanding patient access, optimizing transplantation protocols, and enhancing the feasibility and adoption of islet replacement therapy. Ultimately, my work has the capacity to transform T1D management and significantly improve the lives of individuals living with this condition.