An exercise in skipping

Identifying the problem usually precedes an effective solution. The CEO of Sarepta Therapeutics, speaking to a question during the earnings call for the period ending 31 December 2019, laid out the problem with exon skipping in a no fuss, easy to understand analysis. He described the fact that the base PMO used by Sarpeta has two things going for it and one significant disadvantage.

The two things that work admirably is that its precise and its safe; 'it creates exon skipping, and it creates dystrophin'. The big limitation is that its neutrally charged molecule is passive which creates the need to 'drag' it into cells in 'greater abundance'.

Its true that we know all this but when the CEO of one of the world leaders in RNA therapeutics explains it, particularly when the base PMO was designed by a research team in Perth, it carries a certain gravitas.

We know that Sarepta use a peptide to drag the PMO into the cell nuclei. The effectiveness of the PPMO, however, is constrained by the fact that getting the right dose is proving elusive due to toxicity; 'the one significant question for us is that can we get to those doses.....[that] would develop dystrophin significantly greater than the PMO'.

Simply increasing the dosage isn't an option. Solving the problem in finding the right dose will require a breakthrough in the delivery of the PMO in order to realise the promise of RNA therapeutics. We know all that but it does highlight the importance of the data in the current PYC ocular CPP program.