Gene therapy has the potential to provide a one-time, curative treatment for a variety of liver diseases, including those caused by single gene defects such as Hemophilia A and B, Wilson disease, and alpha-1-antitrypsin deficiency, among others. The liver is an ideal organ for gene therapy because it has a high regenerative capacity and can be accessed relatively easily through the bloodstream.

There are a few different approaches to gene therapy for liver diseases:

1. Gene Addition Therapy: This strategy is used for diseases that result from a missing or defective gene. In this approach, a functional copy of the gene is delivered into cells using a viral vector. For example, Adeno-associated viruses (AAVs) have been used extensively for this purpose. The goal is to provide the cells with a functional copy of the gene they are missing, enabling them to produce the necessary protein.
2. Gene Silencing: For diseases that result from a harmful overexpression of a gene, gene therapy can be used to reduce or stop the production of the problematic protein. RNA interference (RNAi) is a common technique for gene silencing. Small interfering RNAs (siRNAs) or short hairpin RNAs (shRNAs) can be designed to bind to the mRNA of the target gene, preventing it from being translated into protein.
3. Gene Editing: For diseases caused by specific mutations in a gene, gene editing technologies such as CRISPR-Cas9 can be used to correct the mutation in the cells’ own DNA. This is a promising approach, but it’s also more complex and has more potential for off-target effects.

These gene therapy approaches are delivered to the liver cells usually by using viral vectors or non-viral methods such as lipid nanoparticles. For instance, in 2020, the FDA approved a gene therapy for Hemophilia B, which is a genetic disorder that affects the liver’s ability to produce clotting Factor IX. The therapy uses an AAV vector to deliver a correct copy of the Factor IX gene to liver cells.

However, gene therapy is not without risks. The body can mount an immune response against the viral vector, and there’s also the potential for off-target effects, especially with gene editing. Furthermore, the efficiency of transduction (the successful delivery of the gene to the cells) and expression (the cells’ ability to produce the protein from the new gene) can vary. As of my knowledge cut-off in September 2021, these are ongoing areas of research, and the field of gene therapy is rapidly advancing.