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.