What if the human body attacks CRISPR? Can we cheat it?

MIT tech rev 5 Jan 2018“Uh Oh. CRISPR might not work on people”. A title like this on the MIT Technology Review website is not the best way to kick-start the new year. But wait, our motto still stands: keep calm and crispr on.

Matthew Porteus and colleagues at Stanford University have analyzed the blood of a few dozen adults and newborns, discovering that most of them are immune to the basic CRISPR ingredient: the DNA-cutting protein derived from Staphylococcus aureus or Streptococcus pyogenes (SaCas9 and SpCas9 respectively). The discovery, described on the bioRxiv preprint website, is not really surprising. Both bacteria cause infections in the human population at high frequencies, so we have humoral and cell-mediated immune responses to their components. Is this a problem for CRISPR future in gene therapy? Of course yes: the immune system may destroy any edited cells, rendering the therapy ineffective, or it may trigger an inflammatory response resulting in serious toxicity. Can we solve the problem? “It depends” is the right answer, let’s see why. In “ex vivo treatments”, where cells are taken from the patient, manipulated and finally reintroduced, the Cas9 protein would not be exposed directly to antibodies, but this is what might happen instead in certain types of “in vivo treatments”, performed directly into the body. T-cells could still kill the edited cells displaying Cas9 peptides as antigens. But don’t despair yet. Researchers think that delaying the transplantation of edited cells could be a potential solution, because Cas9 would only be displayed transiently, and immune suppression could be used. Furthermore, researchers could engineer recombinant Cas9 proteins that escape immune detection or use Cas9 natural variants derived from other bacterial species that do not infect humans.

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