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Msg 34437 of 34949 at 7/23/2018 6:30:40 PM by

In response to msg 34436 by jtrader87	view thread

Re: Chime in on this

My guess.

LNP delivery gives very good release from endosomes. The evolution of
LNP design by Tekmira was toward better endosome release. The
mechanism, which involves pH dependent ionization of LNP lipids,
mimics mechanisms used by viruses to efficiently escape endosomes to
cytoplasm.

GalNAc delivery gives rapid, focused cell uptake to hepatocytes, but
release of siRNA to cytoplasm is very slow. You need to load much
more into the endosomes to get enough released.

Also relevant here, siRNA delivered using GalNAc conjugation must be
stabilized by extensive chemical modification, whereas siRNA delivered
by LNP can be unmodified.

The greater stability to nucleases and slow continuous release from
endosomes explains the greater durability of activity for the GalNAc
conjugated siRNA.

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