miRNA-Based Therapeutics for Non-Alcoholic Fatty Liver Disease and Obesity-Related Metabolic Disorders
Introduction
Non-alcoholic fatty liver disease (NAFLD) is becoming a highly-prevalent condition that may afflict >60% of adults and children with obesity worldwide. Beyond its inherent health-risk as a rising cause of liver cirrhosis, it may be causally linked to obesity and its metabolic consequences – dyslipidemia, insulin resistance and type 2 diabetes. Although responsive to lifestyle modification (particularly low-carbohydrate diet), such intervention frequently fails in the long-term. Yet, no targeted pharmacotherapy for NAFLD currently exists.
The Technology
Utilizing a mouse model of nutritional obesity and obesity reversal, we identified a set of micro-RNAs – regulatory short RNA oligomers – whose expression levels in the liver are rapidly and differentially responsive to both obesity and obesity-reversal. We reasoned that miRNA-based agents (i.e., – specific mimick and/or miRNA-antagonists) could normalize liver miRNA profile in obesity, mimicking the therapeutic effect of obesity reversal, thereby normalizing liver fat content, dyslipidemia and insulin resistance. In a proof-of-concept approach we have antagonized two miRNAs in the livers of obese mice, to mimic the effect of nutritional obesity reversal. [These two specific antagonized miRNAs increased in obesity and rapidly decreased to normal by obesity reversal]. To antagonize in obese mice the obesity/obesity-reversal increased/decreased miRNAs, respectively, we used modified specific anti-miRNAs. These were administered to nutritionally-obese mice by tail-vein injection, 3 times over a 2-week period (in which mice continued to eat obesogenic diet), paralleling the period of obesity reversal achieved nutritionally. Our initial preclinical results indicate that obese mice treated with the anti-miRNAs, compared to mice administered control miRNA sequences, showed improved fasting glucose, insulin, measures of insulin resistance, lower blood triglyceride content, and lower liver fat.
Advantages
- miRNA-based oligomers are naturally-occurring compounds, highly attractive for their utilization as therapeutic agents. Importantly, a miRNA-based FDA approved drug already exists to treat a liver disease, using the same technology of LNA-modified anti-miRNA122, to treat hepatitis C infection.
- miRNAs have multiple, tissue-selective targets, and this seeming “lack of specificity” is a strength in conditions involving dysregulation of multiple proteins and enzymes.
- We further build on this strength by testing combinations of miRNAs and/or anti-miRNAs, in addition to considering singly RNA oligomers.
Patent Status
US provisional patent application; Filed
Principal Investigators
Prof. Assaf Rudich (MD, PhD), NIBN and the Department of Clinical Biochemistry & Pharmacology and Dr. Vered Chalifa-Caspi, NIBN, Ben-Gurion University of the Negev, Israel.
Collaborator
Professor Evette S. Radisky, Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, USA