Objective
The overall goal of this project is to develop combination therapeutic strategies to protect beta cells from autoimmune attack and restore damaged functional beta cells. Also, this project will develop ways to specifically target the beta cells using novel technology.
Background Rationale
T1D is an autoimmune disease. This means that the immune system — which usually protects against foreign invaders like bacteria and viruses—attacks the body’s insulin-producing beta-cells in the pancreas (autoimmune response). Over time, the beta cells are destroyed by the immune system. People with T1D are dependent on injected or pumped insulin to control their blood-sugar levels to survive. However, exogenous insulin it is not a cure for T1D because T1D patients eventually suffer from serious life-threatening complications. Therefore, there is an urgent need for developing therapies that slow or halt disease progression, prevent it from ever occurring, and reverse it.
Cell replacement therapies hold promise to treat T1D but there are many important hurdles to overcome. Other recent efforts, using biological agents that modify autoimmunity (immune modulating therapies) have repeatedly been noted to prevent beta-cell loss in recently diagnosed T1D and delay disease onset. However, in most patients the effects of immune modifying therapies are short-lived. Therefore, long term combination therapeutic strategies that protect beta cells from autoimmune attack and restore damaged functional beta cells are needed.
New-onset T1D patients have reduced STX4 expression in the residual beta-cells. Further, pre-diabetic mouse islets show low STX4 expression. These findings led us to suspect that restoration of STX4 levels could protect beta-cells from immune destruction in animal models and T1D patients. STX4 acts as an important gatekeeper of insulin release and anti-inflammatory pathway in human beta cells. Thus, we hypothesize that agents that boost/enhance this STX4-regulated anti-inflammatory pathway specifically in beta cells would likely have clinical importance in combination with harmine.
Description of Project
People with type 1 diabetes (T1D) have very few functional insulin-producing beta cells. Replacing lost beta cells that are destroyed by the immune system could restore insulin production, improve glucose control and reduce the risk of long-term complications. Our proposal focuses on combination therapies that improve beta cell function and survival and replace lost beta cells. Our collaborators at Mount Sinai discovered a plant-derived compound called harmine, that can regenerate beta cells in the laboratory. Also, we have found that strategies that boost/restore STX4 prevents abnormal beta cell function and reduces beta cell destruction by the immune system. Further, boosting/restoring STX4 in mice was found to be safe and was associated with improved life span. We will use diabetes animal models to understand if treatment combination with STX4 and harmine will lessen the disease burden. We will also develop technologies to boost/restore STX4 production in human beta cells so that it can be used in the clinic.
Anticipated Outcome
Diabetes animal models will provide proof-of-concept that boosting/restoring STX4 in combination with harmine will protect and restore damaged functional beta cells. Novel strategies to boost/restore STX4 in human beta cells will be successfully identified.
Relevance to T1D
Evidence to date suggests that long-term efficacy in T1D maybe achieved with combinatorial therapies that both modulate the autoimmune process plus preserve the functional beta cell mass. Such combinatorial therapies can improve insulin secretion and reduce the risk of T1D related complications. As a result, T1D patients will experience improved quality-of-life and life span.