5:02 PM
Jan 11, 2018
 |  BC Innovations  |  Tools & Techniques

Immune reaction

Researchers are countering Cas9 immune concerns with new solutions

The beating that gene editing stocks took this week on immunogenicity concerns about Cas9, the technology’s workhorse enzyme, are the latest consequence of the field pushing to run while still learning to walk. The field’s scientists, by contrast, see it as one of many surmountable hurdles they are likely to face.

Last Friday, Stanford University professor Matthew Porteus published a study on the preprint server bioRxiv suggesting a large percentage of the human population has pre-existing immunity to the two enzymes most commonly used for CRISPR-based gene editing: Staphylococcus aureus Cas9 and Streptococcus pyogenes Cas9.

On Monday, the three publicly traded CRISPR drug development companies felt the fallout: Intellia Therapeutics Inc. finished down 11.8% from Friday’s close, Editas Medicine Inc. dropped 10.6%, and CRISPR Therapeutics AG fell 2.7%. By today, Intellia and Editas were still down, closing 7.9% and 3.7% off from last Friday’s close, and CRISPR has recovered.

It was the second time in eight months the stocks took a hit based on a preclinical publication -- a rare if not unheard-of event in other areas of drug development. In May, Intellia, Editas and CRISPR Therapeutics fell 0.5-14% after a Nature Medicine paper described a high off-target mutation rate in mice, raising toxicity concerns for the technology. In that case, stocks recovered within a week, as the paper’s methods and conclusions were questioned.

This time, the concern affects both efficacy and safety, and while the paper is a preprint -- not yet vetted by peer review -- many in the field find its findings plausible. An anti-Cas9 immune response could attack and eliminate edited cells, blunting efficacy. It could also elicit a toxic inflammatory reaction in patients upon first exposure to the therapeutic, much like the immune reactions triggered by pre-existing immunity to the viral vectors used in gene therapy.

Both cases reflect the vulnerability of a field that’s gone from discovery to the cusp of the clinic in under six years, and raised more than $1.1 billion in public and private capital from those companies alone on the basis the technology could lead to cures for many genetic diseases. CRISPR Therapeutics plans to start trials on its ex vivo β thalassemia product CTX001 this year, and Editas is planning to submit an IND midyear for its in vivo Leber’s congenital amaurosis type 10 (LCA10) candidate for blindness.

But academic experts told BioCentury that although the concerns need to be dealt with, they aren’t surprising.

“This was a fully expected observation, since we are all constantly exposed to...

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