Researcher Dr. Adrian Krainer explains the science behind antisense oligonucleotide therapy for SMA.

We want to have expression of the gene. We just want to change the type of protein that it encodes. We want to have higher levels of the full length functional protein instead of the version that it skips exon 7, which happens to be very unstable. And so we're using antisense methodology to change how the splicing machinery processes that RNA in order to get higher levels of the product we want. So you have the splisosome, which is a very large machine that catalyzes the reaction and then you have RNA binding proteins that can either lead it to specific places on the RNA or prevent it from recognizing specific places on the RNA. We call those RNA binding proteins, activators and repressors respectively. So in the SMN1 gene when you have a C, there's an activator that binds to that region, which is near the beginning of exon 7. And in the SMN2 RNA that binding doesn’t occur. And then in contrast there is a repressor that prefers to bind to that region. So it appears that in effect not only do you lack an activator that's calling the splisosome's attention to that region of the RNA, but instead there's a repressor, which essentially repels the splisosome. So it's like a double whammy and therefore recognition of exon 7 becomes very inefficient. When an antisense oligonucleotide binds to the RNA, it may block the binding of an RNA binding protein there. What we have identified is an antisense oligonucleotide that's directed to the intron following exon 7 not far from the exon 7-intron boundary. And when it binds there, it prevents binding of the repressor of splicing. And net effect of that is exon 7 is included much more efficiently.

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