Additional antigene agents RNA interference and ribozymes

RNAi and ribozymes represent two additional approaches to gene silencing/down-regulation with therapeutic potential. RNAi is an innate cellular process that achieves silencing of selected genes via an anti-sense mechanism. It shares many characteristics with the antisense-based approach described above, but also some important differences, e.g. in the exact mechanism by which the antisense effect is achieved. 

CH14 NUCLEIC-ACID- AND CELL-BASED THERAPEUTICS 

RNAi probably evolved initially in primitive organisms in order to protect their genomes from viruses, transposons and additional insertable genetic elements, and to regulate gene expression. The RNAi pathway was first discovered in plants, but it is now known to function in most, if not all, eukaryotes. 

RNAi technology has obvious therapeutic potential as an antisense agent, and initial therapeutic targets of RNAi include viral infection, neurological diseases and cancer therapy. The synthesis of dsRNA displaying the desired nucleotide sequence is straightforward. However, as in the case of additional nucleic-acid-based therapeutic approaches, major technical hurdles remain to be overcome before RNAi becomes a therapeutic reality. Naked unmodified siRNAs for example display a serum half-life of less than 1 min, due to serum nuclease degradation. Approaches to improve the RNAi pharmacokinetic profile include chemical modification of the nucleotide backbone, to render it nuclease resistant, and the use of viral or non-viral vectors, to achieve safe product delivery to cells. As such, the jury remains out in terms of the development and approval of RNAi-based medicines, in the short to medium term at least. 

Certain RNA sequences can function as catalysts. These so-called ribozymes function to catalyse cleavage at specific sequences in a specific mRNA substrate. Many ribozymes will cleave their target mRNA where there exists a particular triplet nucleotide sequence G-U-C. Statistically, it is likely that this triplet will occur at least once in most mRNAs. 

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