Preface [Hot Topic: Nucleic Acid Based Drug as Novel Therapeutics in the Treatment of Human Disease (Guest Editors: G. Grassi and M. Grassi)]

Publisher： Bentham Science Publishers

E-ISSN： 1873-4316|5|4|i-i

ISSN： 1389-2010

Source： Current Pharmaceutical Biotechnology, Vol.5, Iss.4, 2004-08, pp. : i-i

Disclaimer: Any content in publications that violate the sovereignty, the constitution or regulations of the PRC is not accepted or approved by CNPIEC.

Previous Menu Next

Abstract

Despite intensive researches aimed at the treatment of relevant human pathologies such as cancer, cardiovascular and virus mediated diseases, optimal drugs have not yet been identified. In this regards, an attractive and novel therapeutic strategy is based on the use of the so called “nucleic acid based drugs”. These molecules, among which the most actual are represented by ribozymes (Rzs), DNAenzymes (DNAzs) and small interfering RNAs (siRNAs), emerged as potential therapeutics in the last two decades with Rzs (described in Grassi et al. of this theme issue) being the first molecules studied, followed soon after by DNAzs (described in Achenbach et al.; Kachigan of this these issue) and finally by siRNAs (describe in Zentilin et al.; Heidenreich; Scherer et al.; Poliseno et al. of this theme issue), whose therapeutic potential become clear in the last three years. Despite the different mechanisms ruling their biological activities, all these molecules base their action on the ability to recognize, in a sequence specific fashion, a target RNA, triggering its destruction. Thus, they can be used to reduce the intracellular level of a specific RNA coding for a protein which affects cellular metabolism or environment, causing disease. As nucleic acid based drugs can be engineered to reduce the level of virtually any RNA, they have a very broad applicability as therapeutics in several human diseases as detailed in the reviews of this theme issue. Whereas the studies about the therapeutic potential of three classes of molecules, which all base their action on the destruction of deleterious RNAs, may appear redundant, the parallel comparison among them will significantly increase the chances to select the most suitable molecules for each specific disease to be treated. Ribozymes, made by ribonucleotides, have been shown to be effective to knock down gene expression in the cellular environment, however their high costs of synthesis and relative short half-life in the cells, suggested to explore the use of DNAzs which, on the contrary, are made by the less expensive deoxynucleotides. DNAzs, in turn, present the disadvantage of not having the possibility to be expressed from viral vectors, thus significantly limiting their delivery options. Finally, in the case of siRNAs, only limited information about their efficacy is available as investigation on their therapeutic potential just started in the last three years. Preliminary studies, however, indicate that they may work at concentrations significantly lower than Rzs and DNAzs, thus potentially conferring to these molecules higher efficacy. Further studies are required to prove these preliminary observations and to understand whether or not this powerful molecules will become the method of choice for sequence specific knockdowns, or they will just be another tool in the arsenal of nucleic acid based drugs.Another issue, which will require intensive investigation before the practical use of nucleic acid based drugs, deals with the individuation of optimal delivery systems. This consideration rises from the observation that, whereas in in vitro studies these molecules show high biological efficacy, in vivo they tend to have considerably lower effects. To overcome this problem, improvements in the amount of molecules delivered, in the permanence of the active molecule and improvement in the delivery specificity to the diseased cell / tissue, need to be further addressed. In this sense, lentiviral vectors as well as bio-compatible polymers are arising as novel and promising delivery systems for nucleic acid based drugs. Together with the appropriate delivery systems, safety concern related the use of nucleic acid based drug need to be carefully investigated. So far, only limited information are available about the induction of possible unwanted side effects as well as off targeting. In this regards, the evaluation of nucleic acid based drug effects on the expression level of as many as possi