New Era for Splice-Modifying Therapies

The reference to a new era comes from an article by researchers from Murdoch, UWA and the Perron Institute, Antisense-mediated splice intervention to treat human disease: the odyssey continues, published May 2019. The article addresses ASOs in general but my interest is in PMOs in particular - neutrally charged antisense.

PMOs have an excellent safety profile but are rapidly cleared from circulation which infer poor uptake into cells. Despite this limitation, eteplirsen, for instance, has done exceptionally well in providing a therapeutic benefit to patients, and that's despite all the fuss created over its approval. Trial patients for instance continue to benefit with respiratory function decline half that expected from natural history studies. Imagine what could be done in the field of genetic diseases with improved intracellular delivery.

Apparently, improved intracellular delivery isn't wishful thinking. According to the authors, "Systemic delivery of these molecules can be greatly improved by conjugation to cell-penetrating peptides". Its all part of the new era; the odyssey continues but we appear to be finally heading home after an epic journey. Perhaps its all best expressed in a statement from Phylogica's recent Operational Update; "CPP-ASO conjugates hold the promise of the synergy of two powerful technologies that come of age simultaneously". Leaning out of the boat and gazing intently ahead, Odysseus may well exclaim 'is that the clinic coming up'.