University of Pittsburgh researchers have identified key transcription factors involved in alcoholic hepatitis (AH) and developed a novel small interfering RNA (siRNA) to inhibit gene expression and improve hepatocyte function. This novel approach could provide hope to millions at risk of alcohol related deaths annually.
Description
AH is a common cause of liver failure, characterized by hepatocellular dysfunction. AH has a high mortality rate and currently lacking an effective, targeted treatment. Identifying and targeting key transcription factors and gene expression could lead to the development of novel treatment strategies for this disease, reducing the burden of multiple forms of liver failure on individuals, health services, and society.
Applications
• Alcoholic hepatitis (AH)
• Alcohol-induced liver disease (ALD)
• Alcoholic steatohepatitis (ASH)
• Liver failure
• Liver Inflammation
Advantages
As many as three million people per year die due to harmful alcohol use and liver disease. Alcohol-induced liver disease (ALD) can progress to AH and death. A lack of animal models has limited the study of the condition and treatment strategies remain an unmet clinical need.
Through analysis of liver RNA sequencing, the inventors identified key genes involved in AH. This approach allowed them to develop siRNA therapies that target gene expression linked to AH, improving hepatocyte function.
Invention Readiness
Liver RNA sequencing was performed using liver samples from controls and patients with different forms of ALD (early ASH, AH, and explanted livers from patients with severe AH). The results showed that expression of genes associated with hepatocyte function (e.g., metabolism of lipids, bile acid and amino acids, and mitochondrial function) was impaired as the disease progressed. One isoform of hepatocyte nuclear factor alpha, a transcription factor known to regulate genes involved in hepatocyte health, HNF4-P2, was barely detected in normal livers but markedly upregulated in AH hepatocytes. In vitro studies found inhibition of HNF4-P2, using novel siRNAs, restored bile acid synthesis and secretion, improving hepatocellular function. Expression of the main isoform, HNF4-P1 remained unchanged as the disease progressed suggesting that specifically targeting HNF4-P2 using siRNA could be a novel treatment for AH.
IP Status
https://patents.google.com/patent/US10913951B2
