Prevent and Reverse Metabolic Dysfunction-Associated Steatohepatitis and Hepatic Fibrosis via mRNA-Mediated...

Area of Science:

• Hepatology
• Drug Delivery Systems
• Immunotherapy

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis is a growing health concern with limited treatment options.
• Current MASH drug development faces challenges in efficacy and specificity.
• There is a critical need for therapies to prevent MASH progression to irreversible cirrhosis.

Purpose of the Study:

• To develop an mRNA-mediated, liver-specific antibody therapy for MASH and hepatic fibrosis.
• To utilize a targeted lipid nanoparticle (LNP) delivery system for enhanced therapeutic delivery.
• To investigate the efficacy of this novel approach in preclinical MASH models.

Main Methods:

• Development of targeted AA3G LNPs encapsulating mRNA encoding IL-11 single-chain variable fragment (scFv).
• Systemic administration of the mIL11-scFv@AA3G therapy in murine models of MASH and fibrosis.
• Evaluation of liver-specific accumulation, IL-11 pathway inhibition, and therapeutic effects on steatosis, inflammation, and fibrosis.

Main Results:

• The mIL11-scFv@AA3G therapy specifically accumulated in the liver, leading to sustained expression of IL-11 scFv.
• Systemic administration reversed MASH and prevented fibrosis progression in early MASH models.
• The therapy effectively ameliorated steatosis, resolved fibrosis, and reduced inflammation in MASH models with fibrosis, outperforming IL-11 scFv alone.

Conclusions:

• mRNA-mediated liver-specific antibody therapy using targeted LNPs is a promising strategy for MASH and fibrosis.
• The developed LNP platform enables sustained therapeutic antibody expression in the liver.
• This approach holds potential for treating MASH and can be adapted for other liver diseases.