Xconomy: Pre-Existing Immunity to CRISPR Found in 96% of People in Study

Pre-Existing Immunity to CRISPR Found in 96% of People in Study

[Updated October 30, 12:15pm ET with further comment, see below.] The immune systems of a large majority of people could already be primed to attack and possibly even disable a key component of CRISPR-Cas9 gene editing therapeutics (which are quickly moving towards their first human tests), suggests new research published today.

If this finding sounds familiar, it’s because another paper, posted in January before being peer reviewed, reached similar conclusions, plunging stock prices of CRISPR companies—CRISPR Therapeutics (NASDAQ CRSP), Editas Medicine (NASDAQ EDIT) and Intellia Therapeutics (NASDAQ NTLA).

Today’s paper, published in the peer-reviewed journal Nature Medicine, suggests those results from January weren’t a fluke. In the latest research, a team of scientists in Germany exposed blood samples from 48 healthy volunteers to Cas9 (a DNA-cutting enzyme) derived from a bacterium called Streptococcus pyogenes. (Cas9 from S. pyogenes is one of the most common DNA-cutting enzymes used in CRISPR R&D, if not the most commonly used.)

The researchers found that 96 percent of the people in the study had T-cell based immunity against Cas9, and 85% had antibodies against it. Those are higher rates than what the other research team, led by Matthew Porteus of the Stanford School of Medicine, showed in January. The Porteus group found that 65% of donors had antibodies against Cas9 from S. pyogenes, but couldn’t detect T cell activity against that enzyme. Previous research from other teams has shown pre-existing immunity in lab animals.

Michael Schmueck-Henneresse of Charité University Medicine Berlin, who led today’s study, said that he was initially surprised by the 96% finding. “But it made sense because the Streptococcus pyogenes bacterium is one of the most common causes for bacterial infections in humans and we have all been through multiple infections and potentially even been colonized by it,” he wrote in an email.

Porteus said in an email the latest results show that issue of immunity to CRISPR-Cas9 “remains one that needs to be closely considered.”

What does this mean for CRISPR-based therapeutics, which could enter human tests as early as next year? “At this point, we cannot predict what will happen [in humans],” Schmueck-Henneresse said. It will depend on a variety of factors, such as how the CRISPR-Cas9 system is packaged and delivered throughout the body and what tissue is being targeting, he added.

Intellia Therapeutics says it has been on the lookout for T-cell based immunity against its CRISPR system. The company is developing CRISPR as a medicine that’s delivered to the body to treat various genetic diseases. (Its other programs use CRISPR to modify cells outside of the body, where this pre-existing immunity should be less of an issue.) For the in vivo programs, Intellia is using lipid nanoparticles (LNPs) to deliver CRISPR to the liver. Jenn Smoter, Intellia spokesperson, said Intellia researchers have tested their LNPs in lab animals. “We have seen no evidence of T cell-mediated cytotoxicity to the cells expressing Cas9.”

Schmueck-Henneresse urges caution going into clinical trials. He says CRISPR drug developers should minimize the amount of time Cas9 is active in cells, and they could consider giving the first patients immune-suppressing drugs.

Other researchers have also raised a red flag around another CRISPR effect: unintended edits in off-target spots along the genome. But pre-existing immunity to Cas9 is more of a worry than off-target edits, wrote Gaetan Burgio, a genome-editing expert at Australian National University, on Twitter in April, in reaction to a not-yet-peer-reviewed version of today’s study.

[Updated with additional comment] But in a tweet in response to the latest version of the paper, Burgio wrote that there are ways to circumvent the immunity issue.

Published now in @NatureMedicine on #CRISPR & Immunity to SpCas9. 6 months has past since the preprint was online & it is a long time in the CRISPR field. Since then additional work showed how to circumvented this by modifying Cas9 protein or using Cas9 orthologs. So No panic ! https://t.co/S9ZCAElH6X — Gaetan Burgio (@GaetanBurgio) October 30, 2018

Another possible way around the immunity issue is to use other kinds of DNA-cutting enzymes. That may not be a straightforward solution, Schmueck-Henneresse says, because other Cas enzymes come from bacteria that humans are often exposed to. Indeed, his team tested other enzymes such as Cpf1 and found similar immune reactions. He suggests pursuing Cas9 from bacteria that are not known to infect humans.

Still Schmueck-Henneresse says there’s no reason to panic. “Our results are a warning, but immunogenicity has been a problem in the field of gene therapy for a long time,” he says.