Immunostimulation: The Sense in Antisense Technology
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Indian Journal of Biotechnology Vol 2, April 2003, pp 175-183 Immunostimulation: The Sense in Antisense Technology Archana Pandey', Satyendra Mishra/ and Krishna Misra*2,3 'Chemistry Department, C M P Degree College, Allahabad 211 002, India 2Nucleic Acids Research Laboratory, Chemistry Department and 3Centre for Biotechnology, University of Allahabad, Allahabad 211 002, India Received 25 March 2002; accepted 21 June 2002 The post-human genomic era has led to the development of therapies, which specifically target molecular pathways responsible for diseases. The original concept of antisense therapy was to simply turn off gene's activity by a short synthetic DNA sequence, having sequence complementary to mRNA and thus block the production of undesirable protein. However, during the last two decades this concept has undergone miraculous change. Today antisense therapy is on crossroads. The observation that oligodeoxynucleotides containing CpG dinucleotides (CpG DNA) exhibit immunostimulatory effect has lead to their use as therapeutic agents and adjuvants for various diseases. Knowledge gained from studies of the medicinal chemistry of CpG DNA has provided a base for designing the second generation of CpG DNA agents with immunostimulatory activity. The present article reviews the recent developments, which have caused the revival of antisense therapy. Keywords: antisense, immunostimulation, vaccine, oligonucleotide therapy Introduction Antisense therapeutics once appeared a wonderful path to biotech glory. Its allure rested in its simplicity and specificity. It was expected to be an elegant, systematic approach to drug target validation and gene function. The concept of antisense therapy initiated by Zamecnik and Stephenson in 1978 was straightforward; design an oligonucleotide to bind to a gene's mRNA, inhibit its translation, prevent protein expression, thus turn off gene's activity and thereby exert a therapeutic effect. All that needed was to know the gene's or mRNA's sequence. More than two decade's of elusive chase, after the idea of a lightening quick drug discovery method has met with some hard ground. The history of antisense drug development although filled with disappointments, surely has a bright future. Its finest hours are yet to come. The toughest years of antisense development now seem to be ending in this post-genomic era, since the antisense tools are tailor-made. The unraveling of human genome sequence has certainly enabled companies to develop therapies that specifically target molecular pathways responsible for disease. Antisense technology makes it possible not only to identify the role of individual genes in disease but * Author for correspondence: Tel: 0532-2460816; Fax: 0532-2623221 E-mail: [email protected] also to develop specific drugs to treat particular diseases. "The question is not any longer will antisense deliver a drug", says Frank Bennett (Principal Scientist of Antisense Research at Carlsbad, CA based ISIS Pharmaceuticals Inc, San Diego, USA) with confidence "It's what will be the next antisense drug". However, what no one knows and therefore, cannot answer is what would be the impact of antisense drugs on medicine in future. Today antisense technology is on cross-roads. Mechanism of Antisense Therapy In the pathway from gene to protein there are several possible regulatory steps. The process of genetic expression consists of the transcription of antisense strand of DNA (acting like a template) to single stranded mRNA, which now becomes a sense strand followed by mRNA binding to cellular factors (ribosomes) where specific proteins dictated by the genes are made (translation). Many diseases result when either foreign DNA or RNA or inappropriate expression of host DNA generates a disease associated protein. The insertion of viral DNAIRNA sequences into the host cell by retrovirus, results in assembly of new viral particles (Fig. 1). In order to block production of undesirable protein, short synthetic DNA sequences approximately 10-20 nucleotides long having sequence complementary to
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