Recombinant adeno-associated virus 8-mediated inhibition of microRNA let-7a ameliorates sclerosing cholangitis in a...

Area of Science:

• Hepatology and Gene Therapy
• Molecular Biology and miRNA Therapeutics
• Inflammatory and Fibrotic Liver Diseases

Background:

• Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease with limited treatment options, increasing cholangiocarcinoma risk.
• Recombinant adeno-associated virus (rAAV) vectors are a promising gene therapy platform for liver diseases.
• The microRNA (miRNA) let-7a is implicated in PSC progression, but its therapeutic inhibition has not been explored.

Purpose of the Study:

• To evaluate the therapeutic efficacy of inhibiting let-7a using rAAV8 in a mouse model of xenobiotic-induced sclerosing cholangitis.
• To assess the impact of let-7a inhibition on hepatobiliary injury, inflammation, and fibrosis.
• To investigate the downstream molecular mechanisms, including NF-κB signaling.

Main Methods:

• A mouse model of sclerosing cholangitis was established using 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine (DDC) feeding.
• Mice received a single dose of rAAV8-mediated anti-let-7a-5p sponges or a control vector.
• Hepatobiliary injury, inflammation, fibrosis, and let-7a/NF-κB pathway components were analyzed.

Main Results:

• rAAV8 effectively reduced let-7a-5p expression in the DDC-induced mouse model.
• Inhibition of let-7a alleviated hepatobiliary injury, prevented cholangiocyte proliferation, and reduced biliary fibrosis.
• let-7a inhibition upregulated suppressor of cytokine signaling 1 and Dectin1, suppressing NF-κB-mediated hepatic inflammation.

Conclusions:

• Liver-specific inhibition of let-7a-5p via rAAV8 demonstrates potent therapeutic effects in a preclinical model of sclerosing cholangitis.
• This gene therapy strategy holds potential for clinical translation in treating human primary sclerosing cholangitis.