Objective
This project is designed to improve the health and quality of life of people living with type 1 diabetes (T1D). Despite significant advances in therapeutic approaches, a great number of patients living with T1D still develop complications that include poor vision and decreased kidney function. In fact, diabetic retinopathy is the leading cause of vision loss in working-aged Americans, and diabetic nephropathy is a top-10 cause of death in the U.S. The objective of this proposal is to accelerate the development of a new therapeutic to prevent complications in the retina and kidney of people with T1D. To do so, we will investigate the role of important protein known as REDD1 (red-one). Inside cells of the retina and kidney, REDD1 inhibits some of the effects of the hormone insulin. In healthy cells, the amount of REDD1 is very low, because REDD1 normally gets broken down quickly. However, diabetes causes a modification of REDD1, known as protein oxidation, that prevents it from being rapidly degraded. The oxidation of REDD1 acts as a molecular switch that causes it to accumulate in cells of the retina and kidney. The consequences of there being a lot more REDD1 in these cells include chronic inflammation and an inability to properly make antioxidants.
The studies here will explore two different ways to prevent diabetes from activating the REDD1 molecular switch. Initially, we will use a special new laboratory mouse with a genetic mutation that prevents activation of the REDD1 molecular switch. We will make the new mice diabetic and then compare the development of complications in their eye and kidney to regular diabetic mice. We will then identify drugs that bind specifically to the REDD1 molecular switch. Traditionally drug discovery requires tremendous investment of time and money to screen drug libraries and identify lead candidates. Despite significant effort, poor binding of drugs to their target protein results in high failure rates. To address this issue, we will use cutting-edge artificial intelligence (AI) to screen over a billion drugs for their ability to stick to the REDD1 molecular switch. In our preliminary studies, we have already identified three commercially available drugs that bind the REDD1 molecular switch with high affinity and have all the necessary characteristics to work well as a therapeutic. The top computational hits will be validated in protein binding assays and with human cell cultures, and then be used to treat diabetic mice.
Background Rationale
Our laboratory has demonstrated that when mice are genetically manipulated to not have an important protein known as REDD1 they are resistant to developing diabetic complications. This area of research showed so much promise that a drug designed to inhibit REDD1 previously made it to clinical trials. When patients with diabetic macular edema were treated with a small RNA designed to reduce how much REDD1 was being made in the eye, there was a modest improvement in visual function. However, researchers realized that they would need to use a much larger dose of the RNA drug to achieve improved outcomes. Consequently, the approach was abandoned over a decade ago in favor of antibody-based therapeutics that target a growth factor known as VEGF. Unfortunately, only a minority of patients treated with drugs targeting VEGF sustain significant improvement in their vision.
Our laboratory recently made an important discovery that revealed a key flaw in the prior approach used to inhibit REDD1. Specifically, we discovered the way that diabetes causes there to be more of the REDD1 protein in cells of the retina and kidney. The amount of each protein in a cell is the result of how fast that protein is being made versus how fast it is getting broken down. REDD1 is a unique protein because it gets rapidly degraded by cells only a few minutes after being made. In healthy cells, the rates of REDD1 synthesis and degradation are balanced, resulting in a low amount of the protein. In response to diabetic conditions, there is not a change in the amount of REDD1 being made; however, the normally rapid degradation of REDD1 becomes blocked. Consequently, REDD1 synthesis and degradation are no longer balanced and the amount of REDD1 in cells rapidly increases. By understanding how diabetes causes there to be more REDD1 in cells, we now realize that the prior strategy of using an RNA to slow down REDD1 from being made was flawed. Specifically, inhibiting REDD1 from being made is likely to only be partially effective for reducing the amount of REDD1 protein in the context of diabetes, because REDD1 degradation is blocked. A new therapeutic strategy that more effectively prevents the increase in REDD1 protein in cells of the retina and kidney by allowing it to still be rapidly degraded could potentially improve the health and quality of life of people living with T1D.
We recently discovered that diabetes blocks REDD1 degradation by causing a modification known as protein oxidation. Upon oxidation, the shape of the REDD1 protein is changed, so that it is no longer recognized for degradation. The change in REDD1’s shape that occurs in response to its oxidation functions as a molecular switch. This process is like the chemical bonds that are formed when someone has their hair permed, causing it to be curly versus straight. The approach here will use genetic and drug intervention to prevent the shape of REDD1 from changing in the context of diabetes. Our preliminary studies used molecular modeling to identify a mutation in the REDD1 protein that prevents its shape from changing in response to its oxidation. As a result, the new version of REDD1 still gets rapidly degraded under diabetic conditions. We also used artificial intelligence (AI) to do a preliminary screening of chemical libraries to find drugs that stick to the REDD1 molecular switch. In our preliminary studies, we identified three commercially available drugs that bind the REDD1 molecular switch with high affinity and have all the necessary characteristics to work well as a therapeutic.
Description of Project
Microvascular complications are a leading cause of morbidity and mortality in people with type 1 diabetes. This Innovation Grant is designed to improve the lives of people living with type 1 diabetes by developing new therapeutics to prevent microvascular complications in the eye and kidney. Our laboratory recently discovered that diabetes activates a molecular switch on an important protein known as REDD1 (red-one). Under healthy conditions, the amount of REDD1 in cells is very low. However, in response to diabetes, the molecular switch on REDD1 is activated and it rapidly accumulates. The consequences of there being a lot more REDD1 in cells include chronic inflammation and an inability to properly make antioxidants. The studies here will explore ways to prevent diabetes from activating the REDD1 molecular switch. Initially, we will use a special new laboratory mouse with a genetic mutation that prevents activation of the REDD1 molecular switch. We will make the new mice diabetic and then compare complications in their eye and kidney to regular diabetic mice. We will then identify drugs that bind specifically to the REDD1 molecular switch. Traditionally drug discovery requires tremendous investment of time and money to screen drug libraries using a molecular assay to identify lead candidates. Despite significant effort, poor binding of drugs to their target protein results in high failure rates. To address this issue, we will use cutting-edge artificial intelligence (AI) to screen over a billion drugs for their ability to stick to the REDD1 molecular switch. In our preliminary studies, we have already identified three commercially available drugs that are predicted to bind tightly to the REDD1 molecular switch and have all the necessary characteristics to work well as a therapeutic. The top computational hits will be validated in protein binding assays and with human cells, and then be used to treat diabetic mice. This project is expected to have a powerful impact on the lives of people with type 1 diabetes, because it addresses a clinical need for therapeutics that provide interventions in the early stages of diabetes by targeting specific molecular events that cause microvascular complications in the eye and kidney.
Anticipated Outcome
This project is expected to have a powerful impact on the lives of people with T1D, because it addresses a need for therapeutics that provide interventions in the early stages of diabetes by targeting specific molecular events that cause microvascular complications. The proposed project is at the interface of basic science discovery and the development of next-generation therapeutics. The proposed studies are expected to provide evidence for a novel molecular mechanism that causes diabetic complications in the eye and kidney. The studies will identify and validate a new small molecule inhibitor that prevents activation of the REDD1 molecular switch in the context of diabetes. Finally, the studies will explore the therapeutic potential of the new drug in diabetic mice. Following project completion, we will pursue any additional nonclinical safety studies that are necessary for Investigational New Drug (IND) approval from the FDA in hopes of testing its therapeutic potential in clinical trials. Our goal is to develop a new pharmacological intervention to prevent the development of diabetic complications in the eye and kidney. Considering the modest benefits seen in diabetic patients treated with a theoretically inferior strategy for REDD1 inhibition, this project is expected to have a powerful impact on the lives of people living with T1D.
Relevance to T1D
This project is designed to improve the health and quality of life of people living with T1D by developing better treatments. Despite significant advances in therapeutic approaches, a great number of patients living with T1D still develop complications that include poor vision and decreased kidney function. In fact, diabetic retinopathy is the leading cause of vision loss in working-aged Americans, and diabetic kidney disease is a leading cause of death. Thus, there is a clear unmet clinical need for new therapeutics to improve the health of people living with T1D. This project is specifically designed to develop a new drug to prevent diabetic complications in the retina and kidney. To do so, we will explore disease mechanisms in a mouse model of T1D. We will use artificial intelligence (AI) in combination with molecular modeling to identify new drugs to prevent diabetic complications. We will then perform intervention studies with the newly identified drug in human cells exposed to diabetic conditions and in diabetic mice. The goals of this project are directly in line with the JDRF’s mission to improve the lives of people living with T1D by accelerating the development of advanced drugs to improve health outcomes and quality of life.