Periodic Reporting for period 2 - DIRECT Therapies (Diabetes Immunoengineering: Redesigning Encapsulated Cell Transplant Therapies)
Reporting period: 2020-07-01 to 2021-06-30
Diabetes remains a global healthcare challenge, affecting around 370 million people worldwide. For some patients, diabetes is caused by the destruction of the insulin-producing cells by the host immune system. These cells are called beta cells and clusters of these cells are found together in the pancreas, called islets. For a sub-set of Diabetes Type I patients, transplanting donor islets into the patient can help to restore glucose control in some patients. However, like other patients who receive a kidney or lung transplant, these patients have to take immunosuppressive drugs, often daily, for the remainder of their lives to prevent transplant rejection. These drugs can impact the quality of life for the patient, and may lead to an impaired immune system at risk of opportunistic pathogens and increased cancer risk.
There is an unmet clinical need to develop new tools and technologies that can deliver immune suppression locally to protect transplanted tissue from rejection by the immune system. These new materials should simultaneously support transplanted tissues in integrating with the host, whilst allowing the host immune system to function normally in response to infection and disease in other parts of the body. Developing this technology would enable transplant patients to live healthier lives.
The scientific aim of this project was to develop innovative multifunctional materials for diabetes-1 cell therapies; those that can better support islet function and also direct the host immune system. We hoped that these technologies would help us to study how the immune system responds to transplanted materials. Indeed, we found that by developing materials which deliver anti-inflammatory cytokines directly to the transplant niche, we were able to extend transplant lifetimes with reduced need for systemic immune suppression. Our next steps will be to evaluate different delivery systems which can get these immunoregulatory molecules to the right place at the right time.
There is an unmet clinical need to develop new tools and technologies that can deliver immune suppression locally to protect transplanted tissue from rejection by the immune system. These new materials should simultaneously support transplanted tissues in integrating with the host, whilst allowing the host immune system to function normally in response to infection and disease in other parts of the body. Developing this technology would enable transplant patients to live healthier lives.
The scientific aim of this project was to develop innovative multifunctional materials for diabetes-1 cell therapies; those that can better support islet function and also direct the host immune system. We hoped that these technologies would help us to study how the immune system responds to transplanted materials. Indeed, we found that by developing materials which deliver anti-inflammatory cytokines directly to the transplant niche, we were able to extend transplant lifetimes with reduced need for systemic immune suppression. Our next steps will be to evaluate different delivery systems which can get these immunoregulatory molecules to the right place at the right time.
To date, we have tested three parallel approaches to local protection of islet transplants without global immune suppression. These are 1) coating the islets in a hydrogel layer to reduce immune cell recognition, 2) delivering drugs to the transplant site to control the immune system locally, and 3) delivering nucleic acids to the transplant site to provide instructions to the immune system on how to behave when it recognises the islets.
Our preliminary findings indicate that all three of these technological approaches provide a benefit to islet survival and can help to mitigate transplant rejection. Glucose homeostasis was restored in diabetic models that received islet transplants. Briefly, hydrogel coatings provide a barrier that prevents the immune system from being able to reach the transplanted islets. However, a reasonably thick hydrogel coating is needed to protect the islets from the immune system. This coating makes the islets larger than normal, and so we have to carefully consider where they can be transplanted into the body. In approach 2, local drug delivery provides immunosuppression directly to the transplant niche. These systems can help the islets to survive for longer, and reduce the risk of transplant rejection by the immune system. However, the drug supply is exhausted after a few months and so we are now investigating alternative systems with extended delivery and drug reservoirs that may last for longer. In approach 3, we proposed using nucleic acid delivery to provide instructions to the immune system in the transplant niche. We were excited to find that these systems can also protect transplanted islets for a few months. We are now focused on evaluating the longer-term success of these approaches and extending the transplant lifetime. These results will soon be available for the public to read though peer-reviewed scientific publications.
Our preliminary findings indicate that all three of these technological approaches provide a benefit to islet survival and can help to mitigate transplant rejection. Glucose homeostasis was restored in diabetic models that received islet transplants. Briefly, hydrogel coatings provide a barrier that prevents the immune system from being able to reach the transplanted islets. However, a reasonably thick hydrogel coating is needed to protect the islets from the immune system. This coating makes the islets larger than normal, and so we have to carefully consider where they can be transplanted into the body. In approach 2, local drug delivery provides immunosuppression directly to the transplant niche. These systems can help the islets to survive for longer, and reduce the risk of transplant rejection by the immune system. However, the drug supply is exhausted after a few months and so we are now investigating alternative systems with extended delivery and drug reservoirs that may last for longer. In approach 3, we proposed using nucleic acid delivery to provide instructions to the immune system in the transplant niche. We were excited to find that these systems can also protect transplanted islets for a few months. We are now focused on evaluating the longer-term success of these approaches and extending the transplant lifetime. These results will soon be available for the public to read though peer-reviewed scientific publications.
In this project, we aim to develop new technologies that can eventually replace the daily drugs that transplant patients need to take to prevent transplant rejection. We have focused on islet transplantation for diabetic patients. We have shown that all three of the approaches we designed can help to support islet function and extend transplant lifetimes by reducing transplant rejection. However, each of these systems has limitations in their duration of action. In the next project reporting period, we anticipate comparing these technologies more fully and evaluating methods to extend the therapeutic efficacy of each strategy. If successful, the design of new therapeutic approaches to mitigate transplant rejection could be applied to other cell and organoid transplants, and perhaps eventually to whole organ transplant patients.