Novel vectors and approaches for gene therapy in liver diseases

Summary Gene therapy is becoming of increasingly valuable utility to treat many genetic diseases with no or limited treatment options. This is the case for hundreds of monogenic metabolic disorders of hepatic origin, for which liver transplantation remains the only cure. Furthermore, the liver contains at any point in time 10-15% of the body’s total blood volume, making this organ ideal for use as a factory of proteins to be secreted into circulation. In recent decades, an expanding toolbox has become available for liver-directed gene delivery. Although viral vectors have long been the preferred approach to target hepatocytes, an increasing number of non-viral vectors are emerging as highly efficient vehicles for the delivery of genetic material. Here, we review advances in gene delivery vectors targeting the liver and more specifically hepatocytes, covering strategies based on gene addition and gene editing, as well as the exciting results obtained with the use of RNA as a therapeutic molecule. Moreover, we will briefly summarize some of the limitations found in liver-directed gene therapy and potential approaches for overcoming them.