Gene Therapy in Liver Diseases: State-of-the-Art and Future Perspectives

Abstract

Gene therapy is a fundamentally novel therapeutic approach that involves introducing genetic material into target cells in order to fight or prevent disease. A number of different strategies of gene therapy are tested at experimental and clinical levels, including: a) replacing a mutated gene that causes disease with a healthy copy of the gene, b) inactivating a mutated gene that its improper function causes pathogenesis, c) introducing a new gene coding a therapeutic compound to fight a disease, d) introducing to the target organ an enzyme converting an inactive pro-drug to its cytotoxic metabolite. In gene therapy, the transcriptional machinery of the patient is used to produce the active factor that exerts the intended therapeutic effect, ideally in a permanent, tissue-specific and manageable way. The liver is a major target for gene therapy, presenting inherited metabolic defects of single-gene etiology, but also severe multifactorial pathologies with limited therapeutic options such as hepatocellular carcinoma. The initial promising results from gene therapy strategies in liver diseases were followed by skepticism on the actual clinical value due to specificity, efficacy, toxicity and immune limitations, but are recently re-evaluated due to progress in vector technology and monitoring techniques. The significant amount of experimental data along with the available information from clinical trials are systematically reviewed here and presented per pathological entity. Finally, future perspectives of gene therapy protocols in hepatology are summarized.

Hepatocyte Transfection in Small Pigs After Weaning by Hydrodynamic Intraportal Injection of Naked DNA/Minicircle Vectors

“…The presence of such disorders, with defects only in the liver but severe sequelae for the entire body, makes the liver a primary target organ for novel (not only) gene therapeutic approaches. 9,10 Currently available treatment modalities are, at least in the case of metabolic liver disorders, far from being satisfactory since they often address only the symptoms of disease. In addition, several curative approaches were evaluated such as transplantation *Correspondence: Dr. Johannes Häberle, University Children's Hospital Zurich, Steinwiesstr.…”

Lipid Nanoparticles for Gene Delivery

“…Liver diseases, including inherited metabolic disorders, chronic viral hepatitis, liver cirrhosis, and primary and metastatic liver cancer constitute a formidable health problem due to their high prevalence and the limitations of current therapies (Domvri et al, 2012; Gonzalez-Aseguinolaza & Prieto, 2011; Prieto et al, 2004). For most of the inherited metabolic liver diseases, no effective therapy is currently available other than liver transplantation, which is hampered by donor shortage, cost, surgical risks, and long-term immunosuppression.…”

Advanced therapy medicinal products: Gene therapy

“…With the insertion of the gene in cells containing the mutated version you can reset function thus curing disease. But also with gene therapy you can inactivate a mutated gene that is not working properly and even introduce genes that help to fight a particular disease [1][2][3][4][5].…”