Having long been demoted to tool compound status, shRNA is gaining renewed attention as a therapeutic modality by offering a simpler path to creating next-generation cell therapies than gene editing. Celyad has jumped in, using Horizon Discovery’s shRNA platform to launch a new arm of its CAR T cell pipeline.
While siRNA has yielded an approved drug and a growing stack of deal activity, short hairpin RNA (shRNA) has become the poor cousin form of RNAi, virtually absent from the rally for oligonucleotide therapies (see “Amplifying Oligos”).
Both forms of RNAi suppress gene expression by degrading mRNA. siRNA is single-stranded, silences gene expression transiently in the cytosol, and is typically delivered as an oligo via nanoparticles, polymers or conjugates. In contrast, shRNA is double-stranded, stably expressed from a virally delivered DNA sequence in the nucleus, and exported into the cytosol, where it is processed into siRNA.
ShRNA’s stable expression profile makes it a better fit for engineering cell therapies than siRNA, whose effect wears off on the order of days, since the cells cannot be recovered after infusion for re-dosing.
Although shRNA entered the clinic in 2007, it has been largely used for discovery research. Only two companies, Gradalis Inc. and Tacere Therapeutics Inc., have completed trials of therapies involving shRNA.