7:22 PM
Apr 04, 2019
 |  BC Innovations  |  Tools & Techniques

Second shot for shRNA

How tool developers and CAR T cell companies could recharge shRNA therapies

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. Both Gradalis and Benitec Biopharma Ltd., which acquired Tacere in 2012, have ongoing trials of shRNA-based therapies.

Nicola McCarthy, business unit manager at Horizon Discovery Group plc, told BioCentury that initial enthusiasm for shRNA was cooled by the challenge of avoiding off-target effects, particularly from the hairpin structure’s inactive passenger strand.

“ShRNA can work extremely well, as long as you get the right shRNA for your target, such that it’s clean,” she said. “When you get to a position in a field where you have to carefully consider precisely how an agent is working, all of the people who expected a fairly easy ride drop off.”

“This is a tool that allows you to do many of those steps in one single transduction.”

Christian Homsy, Celyad

But the modality is seeing an uptick of therapeutic applications, particularly within cell therapies, because improvements in shRNA design have made it more feasible to take advantage of its straightforward manufacturing and regulatory path.

Celyad S.A. Executive Director Christian Homsy said shRNA’s small footprint makes it well suited for knocking down multiple genes at once, a strategy he thinks will be increasingly used to optimize next-generation CAR T cell therapies.

“This is a tool that allows you to do many of those steps...

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