p53, the so-called “guardian of the genome”, is the most commonly dysfunctional gene in human cancers, due to mutations in the gene itself or in the p53 regulatory network. Thereof, p53 represents an excellent target for therapeutic strategies against cancer. The German team around Florian Kühnel at the Medical School of Hannover has developed an oncolytic adenovirus which specifically replicates and lyses in p53-dysfunctional tumor cells and not in “normal” cells where p53 is fully active (Nucleic Acids Research, May 2009). This was possible by arming the adenovirus with a carefully designed RNAi network – made of concatenated hairpins – against a set of essential viral genes and under the control of a p53 responsive promoter. The trick is simple: when the adenovirus infects cells bearing functional p53, p53 turns on the expression of the RNAi network and virus replication is inhibited; when p53 is not working properly (as in most tumors), the artificial network is not expressed and the adenovirus multiplies and kills the cells. The researchers achieved cell specific p53-dependent virus replication also in vivo, with consequent inhibition of tumor growth in mouse models. This study holds considerable potential for the development of efficient therapies against solid tumors. RNAi networks offer the great advantage to occupying little space compared to protein-based gene regulation and do not stimulate antibody production. Overall this work confirms and supports RNAi networks as a powerful tool for future “molecular surgery” to detect and correct molecular mistakes in our cells. This research was co-funded by the Synthetic Biology collaborative project “Netsensor”, supported by the European Commission 6th Framework Programme (http://netsensor.crg.es). The goal of Netsensor is to design and engineer gene networks to sense and correct alterations in signal transduction pathways with a specific focus on p53 pathways.
Life Science, 6th Framework Programme
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