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Antisense therapy in Modern medicine
Antisense therapy is one of the types of treatment for genetic disorders. The therapy aims at working at the mRNA level and switching off the translation of the protein from the mRNA of a mutated gene. Hence, the antisense drugs are responsible for the silencing of the gene responsible for the disease and thereby have great potential to cure many incurable, genetic diseases. Extensive research is going on in this field to develop antisense drugs for HIV, Cancer, Asthma, etc.

Antisense refers to a stretch of oliognucleotides, which may be DNA or RNA, that is complementary to the mRNA, produced from the target gene. The antisense, then binds to the mRNA and stop the translation and expression of the protein from the mRNA, thereby silencing the target gene, although the exact mechanism by which the gene silencing takes place is not certain. It is proposed that maybe the mRNA and antisense oligonucleotides or ASO form a duplex structure, thereby mediating the cleavage of mRNA by RNAase H. Some other models have also been proposed like the mRNA transport to the cytoplasm being prevented, the formation of triple helix structure by the binding of the ASO with the duplex DNA, inhibiting DNA transcription, inhibition of the splicing of the mRNA, etc. The construction of a proper ASO is very essential and is possible only after the proper study of the genes responsible for the disease and the sequence of the mRNA formed from the transcription of the gene. The site available for the hybridization of the ASO on the mRNA must also be known as then only the ASO can bind to the mRNA and switch off the expression of the mRNA. The in-vivo stability of the ASO is crucial as it has to reach the target mRNA within the cell without getting degraded. The ASO drugs are developed by proper chemical modification to their backbone structure such that they are resistant to the degradation by nuclease and have proper tissue distribution within the body along with good in-vivo half life.

The use of ASO drugs over other drugs is advantageous as the latter usually target the proteins formed during the expression of the disease, while the former works at the gene level. The ASOs being made of nucleotides are much easier to prepare as only the sequence of the mRNA is needed. The ASO target is only of one domain, compared to multiple domains in case of protein related drugs. Hence, the sensitivity of the ASO drugs can be easily measured by scanning or the southern and northern blotting. The manifestation of the diseases in case of the ASO drugs is much less as the mRNA is itself silenced, hence to overcome this silencing the clonal expansion of the cells that is needed takes a long time. The binding of the ASO with the mRNA is by means of hydrogen bonds, which is much more stronger than any other types of forces like Van der Waals force, etc which occurs in case of the binding of the drugs to proteins.

The research on the ASO therapeutics has moved from the pre-clinical models to the clinical trials. Antisense technology has proved to be a formidable tool for the discovery and study of the various physiological and pathological processes within the body. The research going on will refine the drug delivery methods, specificity, and affinity of the antisense therapeutics, which would be a better tool for the treatment of the patients considering the progress in the use of various gene therapies for treating incurable diseases. ASOs are being researched upon for the treatment of different types of cancer, diabetes, Duchanne muscular dystrophy, obesity, different inflammatory diseases like Asthma, autoimmune diseases like HIV/AIDS, different cardiovascular diseases and many other diseases.

Antisense technology has proved to be better method of treatment considering short drug development time and lesser failure in clinical trials compared to other traditional drugs. The approach of the antisense technology is in accord with the latest, emerging technology in the drug development process, technologies based on genome and the integration of the therapeutics with diagnostics. Hence, these advantages put the ASO therapy on a higher scale than the other drugs targeting proteins, which gives scope for further research on the topic. Antisense technology has provided a good base for the research of more new and highly specific therapeutics.
Obesity and antisense oligonucleotide against fibroblast growth factor

One condition in which antisense oligonucleotide (ASO) based therapy is being considered is obesity, as mentioned in the original article in this thread, although the situation is complicated as the molecular mechanisms underlying obesity are complex. Drugs currently available for obesity tend to be based on appetite suppression and many have failed or been withdrawn due to adverse indications. One recent article has addressed the possibility of developing a novel ASO-based strategy against fibroblast growth factor signalling, which would address a need to identify therapeutic agents which could act on peripheral tissues to increase energy expenditure.

ASO against fibroblast growth factor receptor 4 (FGFR4) was used to treat a diet-induced obese (DIO) mouse model. Liver FGFR4 expression was reduced leading to decreased body weight and adiposity both under free-feeding and calorific restriction conditions. The FGFR4 ASO exerted an additive reduction of body weight and adiposity when administered in combination with rimonabant, an anti-obesity agent which blocks endogenous cannabinoid binding to neuronal CB1 receptors. FGFR4 ASO increased basal metabolic rate during free-feeding conditions and prevented reductions of metabolic rate induced by caloric restriction, which can work against weight loss in response to dietary modification. It also increased fatty acid oxidation and decreased lipogenesis. Reduced FGFR4 was determined to induce plasma FGF15 expression which was proposed to mediate the anti-obesity effects of the FGFR4 ASO. Other indicators including plasma glycemia, whole body insulin sensitivity, plasma lipid levels and liver steatosis were all improved by the FGFR4 ASO treatment. Thus FGFR4 ASO treatment is indicated as a potentially novel addition to the armoury of anti-obesity treatment, in combination with either appetite suppression or diet restriction. Further work is on-going.


YU, X.X. et al., 2013. Peripheral reduction of FGFR4 with antisense oligonucleotides increases metabolic rate and lowers adiposity in diet-induced obese mice. Plos One, 8(7), pp. e66923-e66923

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