Objective
Despite decades of research, no drugs targeting disease associated molecular entities and cellular functions are available to treat type 1 diabetes. Apart from the mainstream treatment of insulin injection, other previous approaches to treat the disease involve invasive approaches such as surgical supplementation of insulin producing beta cells from a deceased donor or injection of antibodies against T cells. Our objective was to find a novel therapeutic target and non invasive approach to treat autoimmunity, the root cause of type 1 diabetes. We found a novel molecular mechanism in which blocking a small RNA, called microRNA-146a, prevents T cell-mediated autoimmunity and type 1 diabetes development. The microRNA-146a acts as a regulator of autoimmunity and our data show its role in type 1 diabetes. Targeting microRNA holds high promise as a potential pharmaceutical approach. Based on this, the major objective of this study is to explore the potential of blocking microRNA-146a as first-of-its kind break-through approach to control autoimmune diabetes. We are proposing to use agents to block microRNA-146a to study their protective effects in type 1 diabetes patient’s cells and mouse model of autoimmune diabetes. This objective is expected to yield drugs or drug candidates that have the potential to reach clinical trials as long-sought-after medication for type 1 diabetes.
Background Rationale
The etiology of type 1 diabetes remains unknown. Several anecdotal evidences relates the origin to a viral or bacterial infection triggering T cell mediated immune response, which when remains uncontrolled, diverts toward attacking self tissue, a phenomenon called autoimmunity. These self reactive T cells kill beta cells in the body that produce insulin. A commonly adopted treatment for type 1 diabetes is ciclosporin, an immunosuppressive agent targeting T cells, which delays the necessity for insulin injections. This suggests the existence of severe T cell immune reaction against insulin producing beta cells, which could be targeted to diminish autoimmunity. However, attempts to control T cell autoreactivity in general, have not yielded fruitful results thus far. Blocking total T cells show some promise in delaying type 1 diabetes, however, the long term consequences of blocking T cells such as compromised immune response or possible cancer incidence remain unknown. Our studies show that blocking a small RNA, called microRNA-146a, protects mice from developing type 1 diabetes. We also found that absence of microRNA-146a prevents the attack of insulin producing beta cells in the pancreas by T cells, allowing insulin production and thus preventing hyperglycemia. It also facilitates T regulatory cell function that suppresses autoimmunity. This dual benefit of blocking microRNA-146a is expected to suppress the progress of autoimmunity in type 1 diabetes. This is expected to decrease T cell mediated killing of beta cells, providing an environment for the survival of beta cells, insulin production and protection from type 1 diabetes.
Description of Project
General Audience Summary
Type 1 diabetes (T1D) is a chronic, lifelong disease with approximately 80 people, predominantly children, diagnosed everyday in the United States. Past decade has seen a rise of 25% in the incidence of type 1 diabetes. Currently, more than 200,000 children in the U.S. are living with type 1 diabetes. According to U.S. Centers for Disease Control and Prevention estimates, this number is predicted to rise to 600,000 by 2050. The disease symptoms start as early as 10 days after birth and stay as a lifelong disease reducing life expectancy by 20%. The current health care costs associated with type 1 diabetes is ~$15 billion each year.
In T1D, specific white blood cells (B and T cells) in the immune system become self-reactive (a phenomenon called autoimmunity) and attack the insulin producing beta cells in the pancreas. Insulin is a hormone that controls blood sugar (glucose) levels, and without the appropriate level of insulin, patients develop high blood glucose levels and secondary complications such as blindness, nerve damage, renal failure and amputations. Knowledge of the root cause for T1D is limited, and despite decades of research, currently there is no cure available. Since 1920, the disease management strategy relies on exogenous insulin injections. Insulin over dose, incorrect timing or combination with other drugs such as aspirin can cause hypoglycemia leading to a coma and even death, especially in children. None of the other approaches to diminish autoimmunity offer promise, warranting urgent need of research to reveal new disease mechanisms to develop novel therapies to control autoimmunity in type 1 diabetes.
We discovered a novel mechanism controlling autoimmunity in T1D. We found that a small RNA, called microRNA-146a plays a key role in autoimmunity in T1D. We generated a mouse model of type 1 diabetes that does not possess the microRNA-146a and found that absence of this microRNA prevents T cell attack and destruction of the beta cells needed to produce insulin. We also found that the absence of microRNA-146a supports the function of T regulatory (Treg) cells, another type of T cell that suppresses the self-reactivity of the T cells. Thus, blocking microRNA-146a has a dual benefits in type 1 diabetes; 1. Prevent the autoreactivity of T cells against the beta cells, and 2. Support the activity of Treg cells that stops T cell over-activity.
Here we propose an approach to control the destructive autoimmune mechanism that cause and progress the disease. This new direction of our research focuses on targeting microRNA-146a using both commercial and novel compounds to block its function that promotes autoimmunity in T1D. This will prevent beta cell destruction and represents a novel breakthrough approach to block or diminish autoimmunity in T1D. We developed a mouse model of T1D that lack microRNA-146a and already have completed proof-of-concept foundational studies. We propose here to conduct further preclinical studies using T1D patient cells and our new mouse model of T1D. This study matches with the mission of JDRF, i.e. to study novel T1D mechanisms and develop new investigative methodologies and tools with future translational potential to treat T1D. Knowledge gained through this research has the future potential to lead to a parenteral or oral medication, which to a great extent, will reduce the dependence of children with type 1 diabetes on exogenous insulin and improve their glucose control, mitigating needle tests and daily injections as well as long-term organ damage.
Anticipated Outcome
Based on our preliminary studies, we expect that blocking microRNA-146a will decrease T cell mediated autoimmunity in type 1 diabetes. This project is unique because it proposes a novel drug target and therapeutic approach based on our new solid scientific discovery, which targets autoimmunity, the root cause of the disease. Because we have identified the target and its mechanism, our approach is not based on a hit or miss screening. Thus, based on our studies, we expect that blocking microRNA-146a (a) will decrease the autoimmune functions of T cells of type 1 diabetes patients with minimal effects on other cells in the body, (b) will protect insulin producing beta cells and (c) prevent the progress type 1 diabetes. We will use both commercially available as well custom developed agents to block microRNA-146a and expect to achieve successful inhibition of the autoimmune function of diabetes patient’s T cells and in mouse model. We expect that treatments to block microRNA-146a will also increase the function of T regulatory cells, decrease the killing of pancreatic beta cells by autoreactive T cells and thereby allowing the maintenance of insulin production. We expect that successful completion of this study has the potential to lead to the development of a long-sought-after therapeutic approach targeting a molecular mechanism associated with type 1 diabetes, holding the promise of a better life for children suffering from this incurable disease. Research based on microRNAs as drugs is emerging and is in the early stages of development in the context of type 1 diabetes or autoimmunity. Thus, this study is expected to be a break-through approach in type 1 diabetes treatment.
Relevance to T1D
Development of clinically successful therapeutics to diminish autoimmunity in type 1 diabetes is an urgent need to improve the lives of millions of children suffering from the disease and improve their later life with minimal or no secondary complications. This study discovered a factor, a small ribonucleic acid (RNA) called microRNA-146a, controlling autoimmunity in type 1 diabetes and that blocking this small RNA prevents autoimmune diabetes development in mouse model. We are conducting experiments using blood samples obtained from children with type 1 diabetes registered at our University Hospitals/Rainbow Babies and Children’s hospital. Current technologies enable identification of children at risk of developing type 1 diabetes by screening for genetic markers and autoantibodies in the blood. However, no strategy to block the progression of autoimmunity has been proved clinically successful to date. The options such as transplantation of insulin producing pancreatic beta cells requires a deceased donor and life-long immunosuppressive drugs to prevent rejection of foreign cells. However, such cell transfer is approved only for patients over 18 years of age, leaving children without a therapeutic option. Our approach to target microRNA to limit self-reactivity of T cells and potentially promote T regulatory cell function offers a double-edged treatment to diminish autoimmunity. This will enable the survival of insulin producing beta cells. The drugs blocking microRNA may be formulated as a parenteral or possibly an oral medication, the most child-friendly way to treat type 1 diabetes. This treatment holds the potential to prevent the progression of autoimmunity in children with new onset disease or decrease the severity of autoimmunity in children with established disease. Once the preclinical studies are completed, we will initiate clinical trials lead by physicians at Rainbow Pediatric Endocrine Division at University Hospitals, who has access to over 1200 children with type 1 diabetes.