Nucleic acid-based therapeutics

Nucleic Acids-Based Therapeutics in the Battle Against Pathogenic Viruses... 

The development of nucleic acid-based therapeutics is not as straightforward as researchers had initially anticipated. Stability, toxicity, specificity, and delivery of the compounds continue to be challenging issues that need further optimization. In recent years, researchers have come up with intricate solutions that have greatly improved the efficacy of potential antisense, ribozyme, as well as RNAi-based therapeutics. Clinical trials for all these types of nucleic acid-based therapeutics are underway. So far, data from several trials and studies in animal models look promising, in particular, the therapies that trigger the RNAi pathway. However, history has shown that compounds that do well in phase I or phase II clinical trials may still fail in phase III. A striking example is the nonspecific suppression of angiogenesis by siRNA via toII-Iike receptor 3 (Kleinman et al. 2008). It will become clear in the near future which compounds will make it as a new class of antiviral therapeutics. 

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 summary, the preformed vesicle approach and detergent dialysis procedure have enabled development of nucleic acid-based therapeutics with clinical utility. Further applications of these liposomal systems with new nucleic acid-based therapeutics such as small interfering RNA for gene silencing are being developed and have demonstrated promising results (28). 

Figure 2.1 General approaches to achieving inducible gene expression in nucleic acid-based therapeutic strategies.

Previous sections have discussed a number of inducible promoters and their applications in nucleic acid-based therapeutics. Enhanced regulated gene expression can be achieved by combining several strategies. 

Pharmaceutical Perspectives of Nucleic Acid-Based Therapeutics... 

The editors have assembled a panel of international experts knowledgeable about the intricacies of molecular medicine. This book is an essential guide to aspiring entrants in the various aspects of nucleic acid based-therapeutics as well as a refresher to those scientists already in the gene therapy field. 

Mahato RI, Kim SW (eds) (2002) Pharmaceutical perspectives of nucleic acid-based therapeutics. Taylor Francis, London and New York... 

Until recently, the term biopharmaceutical was virtually synonymous with therapeutic peptides and proteins. However, nucleic acid-based biopharmaceuticals are now becoming increasingly important therapeutic entities. Research into nucleic acid-based therapeutics is currently focused in two main areas ... 

This whole field is still at a largely experimental stage, but holds great potential to revolutionize the treatment and prevention of disease if safe and effective delivery vectors can be found. The delivery of nucleic acid based-therapeutics is the subject of Chapter 14 the following discussion comprises a brief introduction to gene therapy. 

K. Yoshikawa, Y. Yoshikawa, in Pharmaceutical Perspectives of Nucleic Acid-Based Therapeutics, ed. by R.I. Mahato, S.W. Kim (Taylor Francis, London, 2002)... 

Parenteral administration is the primary route of testing delivery for nucleic acid therapeutics irrespective of whether systemic or local effects are desired. However, to some extent, pulmonary and oral routes are also investigated as potential routes for local targeting to treat cystic fibrosis or colonic tissue (171-173). For nonparenteral delivery, the use of pharmaceutical excipients in the formulation is critical. In addition, the production costs of nucleic acid therapeutic-containing drug delivery systems should be minimized. Even for intravenously or subcutaneously injected nucleic acid-based therapeutics, the use of protective carriers is most likely necessary, and advantageous as compared to injection of the naked RNA or DNA. Carriers can be divided into viral or... 

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