Antisense targeting of mRNA

Designing an artificial antisense oligonucleotide that bind with high affinity and specificity to an mRNA is relatively easy. Therefore, it was early recognized that antisense oligonucleotides which bind to and affect mRNA activity might be developed as a new class of therapeutics. Various subtypes of antisense oligonucleotides have been developed and the most prominent subtypes act by inducing a terminating event on the mRNA.

Thus, one class of antisense oligonucleotides recruits cellular RNase H which cleaves the bound mRNA. Another class of artificial oligonucleotides that act by an antisense-based mechanism are siRNAs. These are short double stranded RNAs that recruit cellular RISC, which cleaves mRNAs bound by the antisense strand of the siRNA. RNase H recruiting antisense oligonucleotides and siRNAs causes destruction of bound mRNA. In some instances, this can lead to side-effects caused by off-target binding. In fact, off-target effects have turned out to be a very serious problem for these approaches.

Another class of mRNA targeting antisense oligonucleotides is so-called splice switching oligonucleotides. These do not recruit cellular enzymes such as RISC or RNase H and act by a steric block mechanism, i.e. they prevent the access of the cellular splicing machinery to the mRNA.

Messenger RNA and proteins

Proteins are fundamental for all cellular processes and therefore proteins are a major target for therapeutic development. Indeed, many therapeutic compounds acts by direct binding to proteins to thereby affect the activity of the bound protein…Read More

Antisense targeting of mRNA

Designing an artificial antisense oligonucleotide that bind with high affinity and specificity to an mRNA is relatively easy. Therefore, it was early recognized that antisense oligonucleotides which bind to and affect mRNA activity might…Read More

MicroRNA

MicroRNAs are short single stranded RNAs of about 22 nucleotides that are processed from hairpin shaped pre-cursors and incorporated into the RNA Induced Silencing Complex (RISC). Once incorporated in RISC, microRNAs direct translational repression…Read More

Antisense targeting of microRNA

Therapeutic approaches targeting microRNA pathways have so far focused on inhibiting the activity of a particular microRNA by using antisense oligonucleotide directed to the microRNA (e.g. antimirs and antagomirs) or on microRNA replacement therapy…Read More