Nucleic-acid-based therapeutic agents

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. 

In order to obtain therapeutic agents based on synthetic ribozymes, it is necessary to modify these structures chemically. Such modifications - as in the traditional antisense strategy - should confer resistance to nucleases, selectivity, and proper hybridization and uptake characteristics. In the case of ribozymes, the design of new modified nucleotides becomes more complex, since correct folding of the nucleic acid is needed in order to maintain the catalytic activity. Several studies (e.g.. X-ray structure elucidation and mapping with modified nucleotides) have shown that the presence of the 2 -hydroxyl group at specific positions in the catalytic core is essential for hydrolytic activity. Ribozymes are currently used in larger screens as a... 

The receptors overexpressed by target cells or in the blood brain barrier. This allows a specific delivery of drugs, proteins, peptides or nucleic acids to their target tissue. PLGA-based nanoparticles can increase the efficacy of treatments because of the sustained release of the therapeutic agent from stable nanoparticles. They can improve pharmacokinetic and pharmacodynamic profiles. 

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