Morpholino therapeutic (eteplirsen) targeting exon 51 of dystrophin for treatment of Duchenne muscular dystrophy: one family's clinical trial story on TV news. http://www.wcax.com/story/19277658/2-vt-brothers-battle-deadly-disorder-only-1-can-get-treatment
Very interesting. But two quick points... 1) The linked story is so generalized and sanitised that it makes absolutely no mention of the science that underlies the drug being trialled. Please Register or Log in to view the hidden image! We wouldn’t have known it was morpholino-based if you hadn’t told us. 2) Morpholinos aren’t RNA. Please Register or Log in to view the hidden image! (although they target mRNA) In a former research life I worked with zebrafish, so you won’t be surprised to hear that I used morpholinos a fair bit. I was always very interested (and still am) to see which basic research tool was the first to be developed into a human therapeutic: siRNA or morpholinos. Not just isolated examples, but regular clinical usage. There’s still no winner as far as I can see; both technologies seem to have produced a few products for clinical trials. Oh yeah… exon 51!!!! Wow, that’s a monster gene.
Hi Hercules, No argument about the media stripping out the science for the story. Still, you rarely see the human side of a clinical trial in the scientific reports, so this shows another important side of the clinic -- and raises an ethical dilemma in an unusually stark form. To make it more exciting, the exon-skipping therapeutic for dystrophin exon 51 is a competition in the clinic between Morpholinos (Sarepta Therapeutics) and 2'-O-Me phosphorothioate oligos (Prosensa with GSK). Both groups are running clinicals for Duchenne muscular dystrophy. I'm having fun watching the race. The drug is an unmodified Morpholino targeting splicing. The target gene, dystrophin, has about 78 exons (there are a few splicoforms). The target location is unusual; instead of using the common research trick of targeting a splice junction, this oligo targets a splice-regulatory protein binding site. These are reported to give the highest-efficiency splice rearrangements in dystrophin. The pharma folks have the advantage of studying single target exons and can do oligo walking experiments to discover the best target. Clearly, that approach is out of the budget of must researchers, so the splice junction targets will probably remain the standard for research; while the splice junction might not be the highest efficacy target, it is easier to find than a high-efficiency splice regulatory target. Perhaps, over time, the algorithms for predicting splice enhancer and splice suppressor targets will improve to the point where they are reliable for targeting Morpholinos. For now, folks run several different algorithms and look for agreement - and that's not a sign of a mature and reliable bioinformatics technique. The disease has a characteristic that makes the unmodified-Morpholino approach possible. Dystrophic muscles are leaky, leaky enough that you can put Morpholinos into the blood and they will enter muscle fibers. Usually, when you put Morpholinos into an intact adult organism your primary product is expensive urine instead of a gene knockdown or splice change. In the case of dystrophy, the pathology presents the opportunity. There might be a few more similar cases, such as hemorrhagic fevers. For most diseases, don't expect the bare Morpholino to be functional without addressing improvement of cytosolic delivery. Best wishes, - Jon
