INVITED COMMENTARY Gene Targeting: Roadmap to Future Therapies Lars C. Huber, MD, Thomas Pap, MD, Ulf Müller-Ladner, MD, Renate E. Gay, MD, and Steffen Gay, MD* Address *WHO Collaborating Center for Molecular Biology and Novel Therapeutic Strategies, Department of Rheumatology, University Hospital, Gloriastrasse 25, CH-8091 Zurich, Switzerland. E-mail: steffen.gay@usz.ch Current Rheumatology Reports 2004, 6:323–325 Current Science Inc. ISSN 1523-3774 Copyright © 2004 by Current Science Inc. Introduction With the beginning of the new century, hopes for therapeutic approaches of rheumatic diseases rose out from laboratories around the globe. The exponential development of novel methods in the field of molecular biology gained momentum on our insight into key pathogenetic mechanisms of fre- quently disabling disorders. However, the complex processes leading to chronic and systemic joint destruction, as it occurs in rheumatoid arthritis (RA), is still not fully understood, thus limiting the design of specific therapies. Primordial treatment strategies were empirically ori- ented to interfere with pain and inflammation. Only a few years ago, disease-modifying antirheumatic drugs and novel biologics that target key molecules in the RA pathway, revolutionized the therapeutic options. The specific inhibition of cytokines, in particular tumor necrosis factor-alpha (TNF-α), resulted in an enormous clinical success. However, the long-term effect on the inhibition of progressive cartilage destruction is not yet well established. Moreover, systemic inhibition may interfere with various physiologic processes and bear a certain range of risks. Thus, the development of novel molecular techniques was a further milestone in our approach to understand and treat RA. Gene transfer has the potential to focus on relevant pathomechanisms and to deliver genes into a locally restricted environment. Gene Therapy in Rheumatoid Arthritis Rheumatoid arthritis is not caused by a specific genetic mutation. However, heritable susceptibility to acquire RA along with other genetic factors may contribute to the development of the disease at an individual level. Gene therapy can be defined as the delivery of specific genes to cells for the treatment of diseases. Initially, this tool was designed for the correction of monogenetic disorders that are inherited in a Mendelian pattern and lack a single gene product. Though the scope of diseases that can be tar- geted by gene therapy has been widened, in particular the use of gene transfer to elucidate disease mechanisms on the molecular level, in this context, gene transfer in RA is target- ing more the modulation of a certain pathway than on cor- recting a specific genetic abnormality. Hence, an essential understanding of these underlying pathways is crucial for the successful application of gene therapy. The initiation and destructive perpetuation of RA requires an orchestrated interaction of different cell types. The current pathogenetic model of RA involves the interplay of chronic inflammation, altered immune responses, and synovial hyperplasia, each of them contributing to a variable degree. As possible targets for gene therapy, cytokines, transcription fac- tors, adhesion-molecules, matrix-degrading enzymes, mole- cules regulating apoptosis, and cell-proliferation have been identified so far. Delivery Systems The transfer of genes into target cells can be achieved by var- ious methods. To date, viral systems are most widely used, because of their natural capability of infecting target cells efficiently and to incorporate the chosen transgene into the host genome. Among the viruses used, retroviral vectors are the most prominent. For the purpose of RA treatment, the retroviral gene that is needed to synthesize the viral protein- coat was replaced by the gene of choice and, thus, turns the vector into a replication-defective virus-particle [1]. How- ever, the use of modified retroviruses as vectors has its limi- tations. They are unable to infect non-dividing cells and, if integration occurs at random in loci that harbor proto-onco- genes or tumor-suppressor genes, the potential for inser- tional mutagenesis might be high. In most gene applications, however, the inserted gene has not shown any oncogenic risk [2]. In other cases, one might seek to modify the vector so that it is not as likely to activate juxtaposed genes. Adenoviruses, commonly used for in vivo gene trans- fer because of their ability to infect non-dividing cells, have