DIFFERENT FUNCTIONS OF AON
Dependent on the design an antisense oligonucleotide may have different functions. The ‘genetic patch’ can skip the stop coding (exon skipping) or correct the separation (splice correction).
The schematic overview made by Erwin van Wijk gives a step by step explanation of how RNA therapy works and how the ‘genetic patch’ is applied to specific mutations or exons.
EXON SKIPPING
This methodology is based on covering (skipping) the part of the gene that contains the causal mutation. The result is that the gene and the protein derived from this get a little bit shorter with, hopefully, sufficient functioning left to bring the progressive properties of the disease to a standstill.
By means of a molecular piece of text – a so-called antisense oligonucleotide (AON) – which seamlessly fits the mutated exon, the exon is covered, making it invisible for the cell and, consequently, no longer translatable into protein.
SPLICE CORRECTION
Genes consist of parts containing the code for translation into proteins (exons). These exons are separated from each other by so-called introns, which are removed before starting the translation into protein. This results in introns not being translated.
In case of splicing mutations an intron is not correctly separated from the exon and this creates a pseudo-exon. This leads to preliminary decomposition of the protein.
An antisense oligonucleotide can, if necessary, also cover an intron, thus ensuring correct separation of the intron and exons. Thanks to this correction a complete and well-functioning protein is produced.
