A recent overview in Nature Biotechnology describes
activities of the multiple biotech companies pursuing commercialization of
siRNA-based therapeutics. Other
than a few cases involving local therapy (intraocular injection for example)
most of the projects focused on the liver or on certain solid tumors. The
pragmatic reasons for this are very clear. Systemic administration of siRNA almost always requires use
of lipid or polymer based nanoparticles to protect the siRNA and to enhance its
intracellular delivery. Unfortunately this greatly limits the biodistribution
of the siRNA since, in most tissues, standard ~ 100 nm nanoparticles are too
big to pass across the endothelial barrier that stands between the blood and
parenchymal cells. That leaves the liver and certain rapidly growing tumors
where there are gaps or ‘fenestrations’ between the endothelial cells that
permit the escape of the nanoparticles from the bloodstream. Thus, like the old
apocryphal story about the drunk looking for his wallet under the streetlight,
because that’s where the light is, the various biotechs seek siRNA applications
in the liver, because that’s where the siRNA goes! Now there are plenty of important diseases that are based in
the liver and that may be addressed by siRNA in nanoparticles- that is fine-but
what about all the other tissues? Surely there is a need to find ways to
deliver siRNA to heart, lungs, other GI organs etc, etc. The biotechs run on
short time horizons and need to pursue the path of least resistance in getting
siRNA into the clinic. However, it seems that there is a real opportunity here
for fundamental research on the extracellular and intracellular transport
characteristics of siRNA that could be scientifically interesting and therapeutically
relevant.
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