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Antisense therapy is a form of treatment that uses antisense oligonucleotides (ASOs) to target messenger RNA (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre-mRNA, direct steric blockage, and exon content modulation through splicing site binding on pre-mRNA. [1]
Antisense oligonucleotides can be used to target a specific, complementary (coding or non-coding) RNA. If binding takes place this hybrid can be degraded by the enzyme RNase H. [12] RNase H is an enzyme that hydrolyzes RNA, and when used in an antisense oligonucleotide application results in 80-95% down-regulation of mRNA expression. [6]
An example of this is the repurposing of the antimineralocorticoid and diuretic spironolactone, which was found to produce feminization and gynecomastia as side effects, for use as an antiandrogen in the treatment of androgen-dependent conditions like acne and hirsutism in women. [1] Metformin also causes off-target activity. [citation needed]
Secondly, off target toxicity also represents a big problem. Despite the locus-specific nature of the endogenous asRNAs, only 10–50% synthesized oligonucleotides showed expected targeting effect. One possible reason for this problem is the high requirement on the structure of the asRNAs to be recognized by the target sequence and RNase H.
Gapmer antisense oligonucleotides (ASOs) have the potential to cause unintended, off-target effects. These off-target effects are produced when the gapmer binds to mRNA with a sufficient degree of complementarity to the target mRNA, blocking or down-regulating the translation of unintended proteins. [12] The functional consequences of gapmer ...
It appears that these effects are sequence-specific; as in most cases, if a Morpholino is associated with non-target effects, the 4-base mismatch Morpholino will not trigger these effects. A cause for concern in the use of Morpholinos is the potential for "off-target" effects.
Antisense oligonucleotides were discovered in 1978 by Paul Zamecnik and Mary Stephenson. [5] Oligonucleotides, which are short nucleic acid fragments, bind to complementary target mRNA molecules when added to the cell. [5] [6] These molecules can be composed of single-stranded DNA or RNA and are generally 13–25 nucleotides long.
An anti-sense oligonucleotide (ASO) is a short piece of synthetic DNA complementary to the sequence of a variable target DNA. It acts as a probe for the presence of the target in a Southern blot assay or, more commonly, in the simpler dot blot assay. It is a common tool used in genetic testing, forensics, and molecular biology research.