Objective
The primary objective of this proposal is to develop an effective, safe, and long-lasting Treg therapy for patients with Type 1 Diabetes. To achieve this, I have set three main goals that address the key challenges currently hindering Treg therapy.
1. The first goal is to enhance Treg recognition by introducing a potent T cell receptor specific for insulin-producing cells in the pancreas. This approach aims to improve Treg functionality and potentially enhance therapeutic outcomes.
2. The second goal is to support Treg persistence in the challenging environment of the inflamed diabetic pancreas. To achieve this, I propose to introduce a custom-built receptor that will provide Tregs with pro-survival signals within the pancreas.
3. The third goal is to equip Tregs with the ability to eliminate harmful T cells, known as memory T cells, that may have initiated the disease. Memory T cells are long-lived and resistant to Treg regulation. To accomplish their selective elimination, I plan to use Tregs to deliver the FDA-approved drug Alefacept, which has demonstrated the selective elimination of memory T cells. This approach could enhance the effectiveness and durability of Treg therapy.
Achieving these specific goals will undoubtedly propel us forward towards our objective of developing a safe, effective, and long-lasting Treg therapy for treating and preventing T1D.
Background Rationale
Treg therapy, a promising approach to prevent Type 1 Diabetes (T1D), a disease where the immune system mistakenly attacks the insulin-producing cells in the pancreas, has shown promising results. Tregs, a specialized type of immune cell, play a crucial role in maintaining immune balance and preventing attacks on the body’s own tissues. While earlier clinical trials indicated the safety of Treg therapy for individuals with T1D, its effectiveness in stopping the disease remained limited.
Upon careful examination of both human trials and our earlier successful animal experiments, I identified a key distinction: in the animal studies, the Tregs were meticulously engineered to specifically recognize the pancreas, while in the human trials, they were not targeted. This observation led me to the hypothesis that granting Tregs the ability to specifically recognize and respond within the pancreas may be the pivotal factor in achieving the desired therapeutic outcomes. By enhancing the cells’ ability to locate and control the immune response within the pancreas, we may pave the way for the development of a more effective treatment for individuals with T1D.
Description of Project
Type 1 diabetes (T1D) is an autoimmune disease where the immune system attacks insulin-producing pancreatic beta cells. A promising treatment involves regulatory T cells (Tregs), which naturally help suppress immune responses, but current Treg therapies haven't yet proven fully effective for T1D.
Our team is developing a next-generation Treg therapy that is more targeted and durable. I have already engineered Tregs to recognize a protein unique to beta cells. Now, I aim to overcome two key challenges: the lack of survival signals for Tregs in the pancreas, and the removal of harmful memory T cells that are long-lived and resistant to Treg suppression.
I plan to overcome these issues by manufacturing Tregs that can survive in the inflamed pancreas environment and can specifically suppress memory T cells. I will achieve this by introducing a tunable and custom-built receptors that will allow Tregs to travel to the pancreatic beta cells and receive pro-survival signals. Additionally, I will equip Tregs with the FDA-approved drug Alefacept which can selectively eliminate memory T cells. This will result in Tregs that can efficiently travel to the pancreas, prevent autoimmunity, and eliminate the harmful memory T cells in the pancreas. Together, these innovations could make Treg therapy much more effective at halting or even reversing T1D.
Anticipated Outcome
I anticipate that the results of this proposal will pave the way for the realization of Treg cell therapy as a viable treatment option for patients with Type 1 Diabetes. The experiments meticulously designed here aim to directly assess the efficacy of engineered Tregs in controlling autoimmunity against pancreatic beta cells. I am confident that engineered Tregs will demonstrate the ability to prevent beta cell destruction, persist in the pancreas for extended periods of time, and ultimately prevent the onset of T1D in preclinical animal models.
Relevance to T1D
This study aims to enhance the ability of Tregs to prevent autoimmune diabetes, which has a direct impact on the prevention and treatment of Type 1 Diabetes. If successful, the results of this proposal could serve as a blueprint for designing the next T1D Treg therapy for clinical trials. This represents a new therapeutic avenue with the potential to prevent the development of T1D and even improve islet transplantation outcomes.