Antisense technology

Various disease states are associated with the inappropriate production/overproduction of gene products. Examples include:

• the expression of oncogenes, leading to the transformed state;

• the overexpression of cytokines during some disease states with associated worsening of disease symptoms;

• The overproduction of angiotensinogen, - which ultimately results in hypertension.

An additional example includes the intracellular transcription and translation of virally encoded genes during intracellular viral replication. In all such instances, the medical consequences of such inappropriate gene (over)expression could be ameliorated/prevented if this expression could be down-regulated. A nucleic-acid-based approach to achieve just this is termed 'antisense technology'.

The antisense approach is based upon the generation of short, single-stranded stretches of nucleic acids (which can be DNA- or RNA-based) displaying a specific nucleotide sequence. These are generally termed 'antisense oligonucleotides'. These oligonucleotides are capable of binding to DNA (at specific gene sites) or, more commonly, to mRNA derived from specific genes. This

Figure 14.13 Overview of the concept of the antisense approach: the end goal is the prevention of expression of a particular gene product (invariably a protein) by either blocking the transcription or translation of that gene

binding, in most cases, occurs via Watson-Crick-based nucleotide base pair complementarity. Binding prevents expression of the gene product by preventing either the transcription or translation process (Figure 14.13).

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