Objective
In the SyneRegim project, we will explore the SYNErgistic effect of β-cell REGeneration and emerging IMmune intervention strategies in preventing or treating T1D. Our aim is to identify a combination treatment that both protects the β cells from autoimmune destruction and helps them recover to reinstate autonomous control of blood sugar levels. To achieve this, we will test the hypothesis whether combination therapies in which the autoimmune destruction of β cells is halted with either anti-CD3 or anti-thymocyte globulin, followed by a regenerative drug that increases β-cell numbers and improves β-cell function, called a GLP-1-estrogen hybrid compound, are superior to the immune therapies alone in the prevention and treatment of T1D in animal models.
Background Rationale
Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing β cells in the pancreas are erroneously destroyed by the immune system. People with T1D present to health care providers when they feel ill and have symptoms related to high blood sugar levels. At that moment they have often lost most of their β cells and require insulin injections to control blood sugar levels. Immune therapies are new and promising treatment approaches to protect the remaining β cells from further immune destruction. In this way, immune therapy offers a perspective of sustained help by the surviving β cells in controlling blood sugar levels as compared to a state when all β cells are gone. However, the β cells lost during the immune attack will not come back by themselves, and insulin injections will remain necessary. We will test a novel approach in which we combine two currently investigated immune therapies (i.e., anti-CD3 and anti-thymocyte globulin) with a regenerative treatment (i.e., a GLP-1-estrogen conjugate) to both protect the remaining β cells from autoimmune destruction and help them recover and restore in terms of function and numbers. By exploring the synergistic potential of these combination therapies in mice, we hope to pave the way for a future cure in humans.
Description of Project
Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing β cells in the pancreas are destroyed by the immune system. People who develop T1D often present to health care providers with symptoms related to high blood sugar levels, including excessive hunger and thirst, frequent urination, blurred vision and fatigue. At that moment, they have already lost most of their β cells and require insulin injections to control their blood sugar levels. Immune therapies are novel and promising treatment options to protect the remaining β cells from further immune destruction. By doing so, immune therapy provides help to the surviving β cells in controlling blood sugar levels as compared to a state when all β cells are gone. However, the β cells lost during the immune attack will not reappear by themselves, and insulin injections will remain necessary. To eliminate the need for insulin injections, β-cell numbers and function will need to be restored. The sex hormone estrogen can increase the number of β cells and improve their capacity to produce insulin. By attaching estrogen to another hormone, called glucagon-like peptide 1 (GLP-1), estrogen can be specifically delivered to the β cells, maximizing the effectiveness of the therapy and preventing potential side effects. Therefore, we will test a novel approach in which we combine two currently investigated immune therapies (i.e., anti-CD3 and anti-thymocyte globulin) with a regenerative treatment (i.e., GLP-1-estrogen conjugate) to protect the remaining β cells from autoimmune destruction and help them to recover in terms of numbers and function. The combination therapies in this project will be investigated using an animal model of T1D, the diabetes-prone non-obese diabetic (NOD) mouse, the current best animal model of T1D. This investigation will determine the safety and efficacy of the combination therapies. We anticipate that that the combination therapies will further delay (and possibly prevent) the development of T1D in pre-diabetic NOD mice, and also improve symptoms of high blood sugar levels in NOD mice that already developed T1D compared to the result of using each of the therapies individually. The outcome of this study will hopefully pave the way for a follow-up study investigating the safety and efficacy of the combination therapies in people with, or at risk of developing T1D. Our innovative therapy could alleviate the need for insulin and provide a genuine cure for T1D.
Anticipated Outcome
We anticipate that the combination therapies will further delay the development of T1D in people at risk of developing the disease compared to the result of using each of the therapies individually. We hope that the combination therapies will be additionally effective in some selected individuals and completely protect them from developing symptoms of high blood sugar levels, thereby reducing the overall number of people affected by T1D. In addition, we anticipate that the combination therapies will also be effective in people who have already developed symptoms of T1D, boosting their insulin production and reducing the amount of insulin injections needed to control their blood sugar levels.
Relevance to T1D
Type 1 diabetes (T1D) affects over 9 million people worldwide. The number of people being diagnosed with T1D each year is also increasing, meaning that the overall number of people affected by this illness will become greater in the future, further burdening the health care sector. Given that most people develop T1D earlier in life, the greater majority of people diagnosed with T1D are children, who will require insulin injections and hospital consultations throughout their life span. Although it is now possible to delay the development and onset of clinical symptoms using immune therapies, like anti-CD3, there is still no definitive cure for T1D. However, the effectiveness of immune therapies can be enhanced by combining them with other therapies that address different underlying causes of the disease. A combination therapy that interferes with the autoimmune response that destroys the β cells and regenerates β-cell numbers and function is in our view likely to be superior to the effectiveness of using either of these therapies individually. Consequently, combination therapies could improve the efficiency of immune therapies that are already showing promising results in delaying, preventing, and (temporarily) reversing T1D.