Orphan Diseases and Orphan PMOs, page-4

The FNA presentation points out that delivery is the primary obstacle impeding the approval of OligoNucleotide therapeutics in general, and by extension PMOs aka Morpholinos in particular. Somewhat of a surprise, the delivery challenge can be seen within the prism of PPMO technology developed by Sarpeta, which itself represents world-leading-edge delivery technology.

The article Morpholinos and their peptide conjugates: Therapeutic promise and challenge for Duchenne muscular dystrophy published December 2010 highlights the problem at hand. The authors point out that PPMO chemistry poses a challenge for the determination of an effective and safe dose regimen.

Before looking more closely at the article, there appears to be two issues to consider. Firstly, there is the inherent problem of getting PMOs into cells in the first place. Secondly, peptide delivery carries its own safety problems which appear to be dose related.

Back to the article:

• the nature of the toxicity from peptide delivery is not well understood.
• there appears to be a dose threshold for toxicity. Below the threshold, toxicity is not observed but above it, toxicity is dose-dependent.

So a key question arises in relation to PPMO technology. Sarepta doesn't appear to flag any safety concerns, in fact quite the contrary. Based upon the research findings, the explanation may well be that dosage is below the threshold at which toxicity emerges. However, how close are they sailing to the threshold?

The relevance of the discussion is what does it mean for Phylogica and its ON therapeutics delivery platform. Critically, it highlights the issue of dosage and in turn throws a bright spotlight upon the efficiency and specificity of delivery. If PYC can demonstrate that it can deliver ON cargoes in order to achieve the required level of efficacy but at lower dosage levels, it could well be the difference between approval or the graveyard for another failed ON therapy.