I read your analysis with great interest. When I started the other thread
Vectors going Viral I had no idea PYC could be part of the re-invention of gene therapy; creating an alternative delivery mechanism to AAVs. Reprising the following quote from your research;
"
Consequently, since the beginning of the RNAi therapeutic revolution, the problem to solve has remained the same: Delivery! Delivery! Delivery! Indeed, all other issues with developing siRNAs as a therapeutic modality have paled in comparison to the delivery problem."(Springer & Dowdy, 2018 p.109).
And again;“If the particle is unable to escape the endosome, it enters into a degradation pathway. Basically, it’s game over.” (Akinc, 2009).
Music to our ears: the refrain of delivery, delivery, delivery to the tune of endosomal escape. Before, we go any further, however, lets be mindful why AAVs may potentially be a trojan horse pulled into the nucleus of the cell. I covered two issues in the before mentioned thread but lets recap and add a third;
- many people have pre-existing immunity to viral vectors
- even if they don't the first inoculation of a vector could induce an immune response
- AAVs used in gene therapies may pose a cancer risk refer Virus used in gene therapies may pose cancer risk, dog study hints by Jocelyn Kaiser published 6 January 2020 in science.mag.
The AAV delivery conundrum explains why a number of biotechs and researchers are working on either fixing the problem with AAVs e.g. using CRISPR to improve viral vectors for safer delivery or developing non-viral delivery systems. And this brings us back to PYC.
How good is the news! I was listening to a presentation from the University of Delaware on lipid nanoparticle delivery technology for siRNA and mRNA therapeutics. One of the take home messages was the need to create a delivery system that is capable of two seemingly opposite properties; stable binding but efficient release. The stable binding is required to keep the siRNA payload intact in the extracellular environment without it being chewed up. The efficient release is to access the intracellular space and escape the endosome. Going back to your own research this is just another way of stating
delivery systems for siRNA must overcome three major obstacles: getting the drug to its target in the body, getting it inside the cell, and releasing it.The fact that PYC is pushing into this arena while maintaining its focus on its lead pre-clinical drug candidate is first class science and sound commercial strategy. As SoT said,
PYC are becoming experts at bringing brilliant world leading technology together and making it work.
(20min delay)
