Comment on “Synthetic human ABCB4 mRNA therapy rescues severe liver disease phenotype in a BALB/c.Abcb4 mouse model of PFIC3”

Abstract

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Gene Therapy for Acquired and Genetic Cholestasis

“…BALB/c Abcb4 -/- show similar levels of serum biomarkers as the FVB Abcb4 -/- mice, but with a faster progression of liver fibrosis, leading to early development of primary liver cancers as well as an earlier onset of other complications, such as portal hypertension [ 111 ]. Five repeat ABCB4 mRNA-LNP injections were able to restore ABCB4 expression and biliary PC levels (~42% of wild-type levels), as well as improve serum biomarker levels, liver fibrosis, and hepatomegaly [ 114 , 115 ]. However, these previously described non-integrative vector-based gene therapy strategies may have important limitations, such as loss of transgene expression, either because of loss of viral genomes due to hepatocyte division or because the short half-life of mRNA requires periodic administration to maintain the therapeutic effect.…”

“…First, the administration of repeated doses of the vector could allow the maintenance of the therapeutic effect. However, this is only straightforward for non-viral vectors, such as mRNA-loaded nanoparticles, although it will greatly increase the cost of this therapy [ 115 , 125 ]. For viral vectors, such as AAV, the induction of vector-neutralizing antibodies after the first dose prevents the use of the same vector for additional administrations.…”