Development of a Novel Targeted RNAi Delivery Technology in Therapies for Metabolic Diseases
Abstract
Excessive accumulation of fat in the liver is an alarmingly prevalent condition in the United States associated with lifestyle-associated conditions including obesity and excessive alcohol consumption. While fatty liver can be a relatively benign condition, it is associated with inflammation of the liver, insulin resistance, and diabetes. Fatty liver from obesity or alcohol consumption can also progress to impairment of normal liver function and cause permanent damage of the liver (cirrhosis) leading to the need for liver transplant. Chronic fatty liver is also associated with an increased risk of cancer. While lifestyle changes (diet and exercise, reduced alcohol consumption) can abate progression, there are currently no specific therapies for fatty liver disease. A recently emerging approach to clinical therapies for a variety of diseases is the use of small RNA molecules (siRNAs) that trigger a cellular mechanism that inhibits any desired targeted gene. Virtually any expressed gene that plays a role in disease pathology can be targeted by careful design of siRNA sequences. Use of this novel technology in the clinic is now getting traction in several clinical trials and portends a potential revolution in therapeutics, but getting siRNAs to the right cells in the body remains a major hurdle. However, we have developed a novel microparticle-based siRNA delivery system based on polysaccharide shells that are prepared from common baker s yeast. These glucan-encapsulated RNAi particles (GeRPs) deliver siRNA and mediate gene silencing specifically in immune cells called macrophages that contribute to inflammation in many widespread diseases. We reasoned that delivery of GeRPs by injection might be an effective strategy for targeting of liver resident macrophages known as Kupffer cells that function as first responders in initiating the inflammation associated with fatty liver disease. Our exciting preliminary experiments designed to test effectiveness of injected GeRPs in mouse models of obesity and type 2 diabetes showed that targeting of key regulators of inflammatory gene expression in liver Kupffer cells could significantly reduce inflammation and improve the defective metabolism in these diabetic mice. Our preliminary results thus demonstrate feasibility of a targeted RNAi-based strategy to reduce expression of inflammatory genes or other genes that promote human fatty liver disease. We propose to further develop this siRNA-based therapeutic toward the ultimate goal of a safe, effective treatment of human patients suffering fatty liver disease. The current formulation of our glucan particle-based siRNA delivery system, though effective in mouse and rats, has drawbacks to clinical application in the number and nature of components required for assembly of the particles. However, we have already made progress in designing and testing new ways of generating particles that will be simpler to manufacture and even more effective in delivering siRNA to key cells. We will use a "test and improve" approach to perfecting these particles that will include incorporating new chemical modifications of the particles, ultimately testing their effectiveness in vivo in mice that have non-alcoholic as well as alcohol-induced fatty liver disease. Success in these experiments would be a major advance toward clinical trials of a specific and effective therapeutic strategy to address the burgeoning healthcare problem of fatty liver disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510569
Entities
People
- Michael Czech
Organizations
- United States Army
- University of Massachusetts Medical School