Gene Therapy Reprograms Cells to Reduce Liver Fibrosis

Fibrosis taken as a whole and in its surrounding context is more complicated than simply a matter of the wrong cells growing in the wrong place, but that is an important portion of it. The condition involves excess connective tissue forming in organs, a type of scarring process, and this degrades organ function. It is a notable component of both chronic liver and kidney disease, for example. Here, researchers demonstrate cellular reprogramming via gene therapy in mice that turns some of the connective tissue cell lineages into liver cell lineages, thus reducing the progression of fibrosis and restoring some of the lost liver cells:

Liver fibrosis, a form of scarring, develops in chronic liver diseases when hepatocyte regeneration cannot compensate for hepatocyte death. Initially, collage produced by myofibroblasts (MFs) functions to maintain the integrity of the liver, but excessive collagen accumulation suppresses residual hepatocyte function, leading to liver failure.

As a strategy to generate new hepatocytes and limit collagen deposition in the chronically injured liver, we developed in vivo reprogramming of MFs into hepatocytes using adeno-associated virus (AAV) vectors expressing hepatic transcription factors. We first identified the AAV6 capsid as effective in transducing MFs in a mouse model of liver fibrosis. We then showed in lineage-tracing mice that AAV6 vector-mediated in vivo hepatic reprogramming of MFs generates hepatocytes that replicate function and proliferation of primary hepatocytes, and reduces liver fibrosis. Because AAV vectors are already used for liver-directed human gene therapy, our strategy has potential for clinical translation into a therapy for liver fibrosis.