Modulation of gene
expression with siRNA has thus far failed to live up to its potential for
therapeutics. After early work created great excitement and lured several major
pharmaceutical companies to enter the field, by 2010 there was a mass exodus as
the many problems with these complex molecules became apparent. A few diehards persisted, particularly the
biotech company Alnylam in Cambridge, MA.
Now Alnylam has been rewarded for its
persistence with a $700M investment from Sanofi. This focuses on Alnylam’s
promising work in treatment of transthyrein-familial amyloid
polyneuropathy, an important orphan disease.
One
of the major problems with siRNA was the inability to effectively deliver these
molecules to their intracellular targets. One approach to this has been to load
the siRNA into cationic lipid nanoparticles. However, this often resulted in
considerable toxicity. Recently Alnylam, as well as several academic labs, have
been making ligand-siRNA conjugates that promote siRNA uptake by receptor- mediated endocytosis. An advantage of
this approach is that ligand-siRNA conjugates are chemically defined molecules,
unlike complex, multi-component nanoparticles. However, the jury is still out on the therapeutic
viability of this approach.
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