Methods and Findings in Experimental and Clinical Pharmacology
Vol. 24, Suppl. A, 2002, pp. 3
ISSN 0379-0355
Copyright 2002 Prous Science, S.A.
CCC: 0379-0355/2002
http://www.prous.com

The Potential of Gene Therapy in the Treatment of Liver Diseases

J. Prieto

Department of Internal Medicine, Division of Hepatology and Gene Therapy, Clínica Universitaria, University of Navarre, Pamplona, Spain

Gene therapy is a new therapeutic procedure based on the transfer of genetic material into cells with the aim of inducing a favorable biological effect. To facilitate the entry of DNA molecules into the cells, the genetic material must be included in molecular constructs called gene therapy vectors, which may be viral or nonviral. Generally speaking, viral vectors are preferred because of their greater efficiency in cell transduction. Depending on the duration of the transgen's expression, vectors are classified as long-expression vectors (months, years) or short-expression vectors (days). The retroviruses, adeno-associated viruses and "gutless" adenoviruses belong to the former category while the first generation adenoviruses or Semliki viruses belong to the latter. Gene therapy is a highly adaptable procedure that can be used to treat single-gene hereditary diseases or acquired diseases such as malignancies, infectious diseases or inflammatory or degenerative processes. In the field of hepatology and gastroenterology, gene therapy has aroused considerable expectation because of its possible applications in the treatment of inoperable tumors, chronic viral hepatitis and liver cirrhosis.

A considerable amount of clinical and preclinical work is currently being performed to develop gene therapy strategies against digestive tract tumors. A range of therapeutic genes are being used, including suicidal genes (which turn an atoxic prodrug into a substance able to induce cell death), tumor suppressor genes, genes that stimulate an antineoplastic immune response and genes that code for antiangiogenic factors. Data provided by pilot clinical trials have shown limited efficacy for suicidal and tumor suppressor genes. However, the antineoplastic activity of IL-12 is raising considerable hopes, in that it combines powerful antiangiogenic effects with its immunostimulant properties. However, this cytokine is toxic when given as a recombinant protein at therapeutic doses. Gene therapy considerably broadens the treatment window, as taking the gene directly to the tumor allows to obtain a high local concentration with low systemic concentrations, thereby maximizing the antineoplastic effect and minimizing adverse systemic effects

A clinical trial is currently underway in our hospital using repeated intratumor injections of an adenovirus that codes IL-12, while another trial is being performed using repeated intratumor injections of dendritic cells taken from the patient and engineered with the IL-12-producing adenovirus. These trials are being carried out in patients with liver cancer, metastatic lower bowel cancer and inoperable pancreatic cancer. The results of these studies will provide us with the necessary data to design new strategies and new vectors that increase the procedure's effectiveness. It is likely that progress in treatment will be achieved through the clinical development of long-expression vectors with regulatable promoters, the introduction of recombinant vectors with a selective replicative capacity in tumor cells and the identification of the genes or combination of genes showing greatest antineoplastic efficacy.

Gene therapy also offers an enormous potential in the treatment of chronic viral hepatitis that is resistant to the current antiviral therapies. The possibility of transducing liver cells using long-expression vectors containing the interferon gene under the control of an inducible promoter may provide high drug concentrations within the liver and low systemic concentrations. This will enable higher interferon concentrations to be achieved where they are needed without unduly increasing the blood levels. Preliminary studies in animal models show that this treatment system is possible and is more effective than the subcutaneous administration of the recombinant protein.

Methods and Findings in Experimental and Clinical Pharmacology Vol. 24, Suppl. A, 2002, pp. 3
ISSN 0379-0355 Copyright 2002 Prous Science, S.A. CCC: 0379-0355/2002 http://www.prous.com