Will human immunity to Cas9 make CRISPR useless?

This paper shows that a large fraction of humans have antibodies agains Cas9. This is not a surprise. Why? Because Cas9 is a bacterial protein, and its common bacterial sources (Staph and Strep) colonize or infect most humans at some point in their lives. Even though Cas9 is an intracellular protein, lysis of bacterial cells or engulfment by white blood cells could activate the adaptive immune system against it. This isn’t true of all bacterial proteins, so it wasn’t an inevitable result, but it’s not surprising either. It is a bit surprising that no one has checked on this before.

Or maybe it just hasn’t been published. I suspect that the companies seeking to commercialize CRISPR-Cas9 have known about this phenomenon for a while (the experiments are not hard to do) and have chosen not to publish the results. Perhaps they were trying to avoid blowback from investors (dumb money is easily spooked), but more likely they were just trying to get ahead of their competitors in devising a fix.

Immunogenicity of non-human therapeutic proteins is not a new problem in drug development – it dates back to the 1880’s. Anti-serum treatments for diphtheria and tetanus (usually produced from horse serum), caused severe tissue necrosis due to immune reactions between horse and human proteins.

More recently, development of monoclonal antibody therapy was hindered by HAMA (human anti-mouse antibody) reactions. The first monoclonal antibody therapy, muromonab, could only be used in immunosuppressed patients. That was in 1986, about 10 years after monoclonal antibody technology had been invented. HAMA was then a significant obstacle to developing monoclonals for therapy.

Today it is no obstacle at all. There are about 70 approved monoclonal antibody therapies. The technology to mask mouse antibodies from the human immune system has matured and is a routine part of drug development. All it took was a decade and a few hundred million dollars.

These technologies – principally changing protein sequences to make them less immunogenic – can be applied to Cas9. So can other immune-masking technologies such as pegylation, or liposome encapsulation. Or packaging in a virus. Some sort of packaging or encapsulation technology will be necessary anyway as part of the delivery technology required to get CRISPR-Cas9 complexes into tissues and cells.

From The Australian

Problems like this are why it typically takes 10–15 years for technological “breakthroughs” in medicine to be translated into therapies. Transitioning a technology from the simple, controlled environment of the lab into the messiness of the clinic is hard, hard work.

But it’s just work, no magic is required. If CRISPR-Cas9 technology fails, it won’t be because of this.

PS – the use of CRISPR for ex vivo editing of immune cells, stem cells or embryos is completely unaffected by anti-Cas9 immune reactions.