University of Pittsburgh and University of Pennsylvania researchers have optimized novel transcriptional therapy to treat end-stage liver disease (ESLD). Using lipid nanoparticles (LNPs) with recombinant mRNA encoding HNF4a2, a transcription factor that regulates much of the gene expression in the liver, hepatocyte cell function in patients with ESLD can be improved. Building on previous work, the mRNA design has been optimized to further improve production of HNF4a2 in hepatocytes in diseased livers and could be a novel approach to reversing ESLD.
A hybrid mRNA sequence, Human coHNF4a-variant 1, has been developed and found to efficiently express the key transcription factor, HNF4a2, in hepatocytes. Expression of HNF4a2 can improve hepatocyte function in damaged livers and could offer a potential therapeutic approach to ESLD.
Description
Chronic liver disease (CLD) remains a leading cause of deaths with over one million annual global fatalities. ESLD develops in patients with CLD when the liver becomes damaged beyond repair. In the absence of a liver transplant, life expectancy can be less than two years. There is a pressing clinical need to develop alternatives to liver transplantation as therapies for ESLD. This novel approach is designed to harness the unique ability of the liver to regenerate and self-repair. Through the delivery of LNPs encapsulating mRNA to express HNF4α2, hepatocyte function in damaged livers can be improved, leading to liver repair and overall improved liver function.
Applications
• End-stage liver disease (ESLD)
• Cirrhosis
• Targeted cell reprogramming
Advantages
A global shortage of livers suitable for transplantation means limited accessibility to liver transplants (LTs) for patients with ESLD. Even when accessible, LTs are not without risk with many patients experiencing complications including organ rejection and an increased risk of infections and other medical issues due to the required anti-rejection medication regimen.
Previous work discovered an mRNA sequence delivered to hepatocytes could over-express HNF4α2, resulting in cell-based transcriptional reprograming. The mRNA sequence has since been optimized. This new mRNA encodes HNF4α2 incorporating isoforms 1 and 2. Transfection more efficiently activates HNF4α2 production compared to existing technology.
Invention Readiness
A novel mRNA sequence, Human coHNF4α-variant 1 (hybrid mRNA), was produced. Hepatocytes from explanted liver samples from three humans with CLD were transfected with varying dosages of hybrid mRNA by lipofectamine. This novel hybrid mRNA induced HNF4α2 protein expression at higher levels than previously studied mRNA sequences.
IP Status
Patent Pending
Related Publications
Tafaleng, E. N., Mukherjee, A., Bell, A., Morita, K., Guzman‐Lepe, J., Haep, N., Florentino, R. M., Diaz‐Aragon, R., Frau, C., Ostrowska, A., Schultz, J. R., Martini, P. G. V., Soto‐Gutierrez, A., & Fox, I. J. (2021). Hepatocyte Nuclear Factor 4 alpha 2 Messenger RNA Reprograms Liver‐Enriched Transcription Factors and Functional Proteins in End‐Stage Cirrhotic Human Hepatocytes. Hepatology Communications, 5(11), 1911–1926. https://doi.org/10.1002/hep4.1763
