Lipid Nanoparticle-Encapsulated mRNA Promising for Liver Repair

By Marilynn Larkin

February 05, 2021

NEW YORK (Reuters Health) - Lipid nanoparticle-encapsulated messenger RNA (mRNA-LNP) delivered regenerative factors and induced recovery in mice with damaged livers, paving the way for further development for humans, researchers say.

"There are currently no FDA-approved drugs to prevent progression of liver disease," Dr. Valerie Gouon-Evans of Boston University told Reuters Health by email. "We provided proof-of-principle that nucleoside-modified messenger RNA complexed with mRNA-LNP, recently used to develop the FDA approved COVID-19 vaccines, is an effective delivery tool to induce robust and timely controlled expression of liver regenerative factors for about three to four days after injection."

"This is a sufficient time frame to treat features of chronic liver injury such as steatosis and to accelerate liver repair in acute acetaminophen-induced liver injury," she said.

In two mouse models of liver injury, the team injected epidermal growth factor (EGF) and hepatocyte growth factor (HGF) - both necessary for liver regeneration - as messenger RNAs encapsulated in small lipid vesicles. The mRNA-LNP attracted mouse hepatocytes, inducing them to transiently express these factors, as Dr. Gouon-Evans noted.

In the NAFLD model, injections of both HGF and EGF mRNA-LNP reversed steatosis and accelerated restoration of liver function, according to the Nature Communications report.

Similarly, in the acetaminophen liver injury model, injections of both HGF and EGF mRNA-LNP accelerated liver regeneration.

Dr. Gouon-Evans said, "Safety has been demonstrated in clinical trials for cancer immunotherapies and the current COVID-19 vaccines from Pfizer-BioNTech and Moderna. Our next step is to collaborate with biotech companies to initiate preclinical studies and develop the novel application of mRNA-LNP to treat chronic and acute liver diseases in humans."

Dr. Malcolm Alison of Queen Mary University of London, UK, who is familiar with the team's work but was not involved in it, told Reuters Health, "Intravenous injection of two nucleic acids can reverse these potentially life-threatening conditions that our habits impose on the liver. These discoveries could have a major impact on clinical practice since the incidence of fatty liver is reaching epidemic proportions in Western society."

Administered as proteins, he noted, EGF and HGF "would have lasted less than one hour. But in their mRNA form they get converted to their growth-promoting proteins by the receptive cells for up to three days - hence, fewer injections."

"In the case of NAFLD mice, the growth factors immediately reduced the liver's fat content while the release of liver enzymes into the blood, an indicator of hepatocyte damage, was also much reduced," he said. "In the case of acetaminophen poisoning, the growth factors also reduced liver enzyme release and accelerated the removal of damaged liver cells, reducing the likelihood of liver failure-induced patient death."

"This study has shown that it is feasible, by simple intravenous injection(s) of growth factor mRNAs, to reverse potentially lethal complications of common lifestyle habits," he concluded.

SOURCE: Nature Communications, online January 27, 2021.