Advancement of CRISPR-Based Adipose Tissue Therapies for Type 2 Diabetes to Nonhuman Primates
Abstract
Overview of This Focused Program: This project addresses the severe problem of type 2 diabetes (T2D) in our general population and in our Veterans. T2D is the most common form of diabetes, affecting a remarkable 1 in 10 adults in the U.S. It is a chronic disease that causes many damaging complications, including blindness, amputations, kidney disease, and heart disease. Its toll on our healthcare system is also tremendous. In recent years, the U.S. spent over $250 billion for treatment of T2D and its complications or over $350 billion when loss of productivity due to inability to work is included. That amounts to over $1,000 a year for each American. The most alarming aspect of this statistic is that it is about 50% higher than it was in 2007, and if these trends continue, it will be catastrophic by 2050. Already, about 75,000 amputations of foot, toe or leg per year are performed in the U.S. based on wounds not healing due to diabetes. One would think that curing T2D would be a simple matter of losing some excess weight, for example, with diet and exercise, since T2D is related to weight gain. But this is not always true. Many individuals develop T2D with only little weight gain, and losing those few extra pounds is almost impossible, especially as we get older. In India, even larger numbers of the population have T2D, despite the fact that most people are thin by our standards. We believe that the real cause of diabetes is not excessive overall adipose tissue, but the development of unhealthy forms of adipose tissue. Our proposal seeks to turn “unhealthy” adipose tissue into its “healthy” form that burns rather than stores fats, using very new methods that can isolate, expand, and change the adipose tissue into healthy therapeutic adipose tissue that can be implanted back into a patient in relatively small amounts. Adipose tissue has many different and important functions. For example, fat is in our heels, providing important mechanical support for walking and running. Fat is also near our intestines, providing protection from microorganisms in our digestive system. The form of fat that is under our skin (“white”) is useful for storing extra energy to use during fasting or exercise. But there is also a form of fat called “beige” fat that keeps our heart and blood vessels warm, and also produces hormones that keep our metabolism healthy. Importantly, very little or no “beige” fat can be found in people with T2D, suggesting that the absence of “beige” adipocytes (the fat cells that make up fat) may be causing the disease. Importantly, “beige” adipocytes have active genes that increase metabolism, burn fat, and produce healthy hormones, while “white” adipocytes do not. Scientists in this Focused Program project have shown that implanting relatively small amounts of “beige” fat cells into fat fed obese mice alleviates diabetes, and they have extended this to human “beige” fat cells that they can obtain and greatly expand from small samples of human adipose tissues. Implanting these human fat cells into “humanized” mice that accept these transplants also alleviates diabetes. This suggests that “beige” fat cells can themselves potentially be a therapeutic—a cell therapy for obesity and T2D. However, these successful mouse experiments need to be advanced to testing in nonhuman primates such as monkeys that are known to also become diabetic as they age and become somewhat overweight. This is the major overall goal of this Focused Program comprised of four interdependent projects. If this goal of succeeding in monkeys can be achieved here, it could lead to clinical trials of this adipocyte cell therapy in human subjects and potentially to realization as a therapy. In order to attack this overarching challenge of alleviating T2D and obesity in monkeys by implanting small amounts of “beige” adipocytes, we have assembled a world-class group of scientists with unique skills and demonstrated accomplishments. Each brings spe
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110565
Entities
People
- Michael Czech
Organizations
- United States Army
- University of Massachusetts Medical School