Abstract
The rapid progress in the field of genomics is increasing our knowledge of multi-gene diseases. However, any realistic hope of gene therapy treatment for those diseases needs first to address the problem of co-ordinately co-expressing several transgenes. Currently, the use of internal ribosomal entry sites (IRESs) is the strategy chosen by many researchers to ensure co-expression. The large sizes of the IRESs (~0.5 kb), and the difficulties of ensuring a well-balanced co-expression, have prompted several researchers to imitate a co-expression strategy used by many viruses: to express several proteins as a polyprotein. A small peptide of 18 amino acids (2A) from the foot-and-mouth disease virus (FMDV) is being used to avoid the need of proteinases to process the polyprotein. FMDV 2A is introduced as a linker between two proteins to allow autonomous intra-ribosomal self-processing of polyproteins. Recent reports have shown that this sequence is compatible with different sub-cellular targeting signals and can be used to co-express up to four proteins from a single retroviral vector. This short peptide provides a tool to allow the co-expression of multiple proteins from a single vector, a useful technology for those working with heteromultimeric proteins, biochemical pathways or combined/synergistic phenomena.
Highlights
For the last 20 years, the gene therapy field has centred many of its efforts on finding ways to deliver a therapeutic gene to certain target cells in order to produce a therapeutic result
During the 1990s, most those strategies were abandoned in favour of the internal ribosomal entry sites (IRESs)
In bicistronic mRNAs bearing an IRES sequence, the first cistron is translated by scanning ribosomes that enter via the 5' end
Summary
For the last 20 years, the gene therapy field has centred many of its efforts on finding ways to deliver a therapeutic gene to certain target cells in order to produce a therapeutic result. IRESs were the first strategy that met with some success, and several polycistronic vectors able to co-express up to 4 genes were developed during the 1990's [2]. Two main problems blocked the successful use of large and complex polycistronic vectors: the large size and imbalance of most IRESs which makes it very difficult to predict the level of expression of the downstream cistron [3]. This commentary discusses several recent publications that use self-processing polyproteins as a novel strategy for co-ordinated co-expression of several genes
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