Gene editing could be the future, but doctors think humans might be immune to it

Yellow caution flag raised

Our body's own immune system could present a roadblock to the efforts of medical researchers who aim to develop gene therapies based on the genome-editing tool called CRISPR-Cas9.

The genome editing tool topped a few lists of the best science developments in 2017 and it's poised to garner great interest this year as well. It's been called a revolutionary tool to remove and repair DNA and add new genes, quickly and easily. The tool is like a Swiss Army knife, versatile enough to cut just a single letter of DNA or to insert several. 

What we found, and it was somewhat surprisingly, is that adult human beings have developed immunity to the Cas9 proteins that we generally have been using to do genome editing.- Dr. Matthew Porteus

But earlier this month, Dr. Matthew Porteus, a pediatrician and stem cell biologist at Stanford University in California and his colleagues raised what he called a yellow caution flag. He identified a potential problem in applying the CRISPR-Cas 9 tool in human patients that could render the technology's amazing potential null and void.

"What we found, and it was somewhat surprisingly, is that adult human beings have developed immunity to the Cas9 proteins that we generally have been using to do genome editing," Porteus said. 

Our immune system is designed to recognize infections. One of the main tools that scientists use to do genome editing, Cas9, is derived from bacteria that commonly affect humans. Typically, Cas9 comes from Strep pyogenes bacteria that cause strep throat or Staph aureus bacteria that often live on our skin. MRSA is a superbug form of a staph infection. 

"We're waving a flag that says this is an issue that we should begin to pay attention to in a way that it has not been paid attention to prior."

Rushed to post

Porteus believed it was so important to raise the flag to get other scientists to evaluate, consider and build on the findings that he and his team posted the study on a pre-print server while the process of peer review continues. In peer review, other experts in the field provide feedback on the article and tell the journal's editor whether or not they think the study is worth publishing. It's a form of quality control. 

The experiments explored the two parts of our immune system:

• The antibody part, or what's known as the humoral immune system. The researchers found about 70 per cent of healthy adults had detectable antibodies that recognize Cas9 and would probably destroy it before it had any effect.
• The cellular or T-cell immunity that recognizes foreign invaders and kills them. The researchers found about half of humans had T cells for Cas9 from Staph aureus. They weren't able to detect T cells that recognized Cas9 from Strep pyogenes.

The findings mean that interruptions from our immune system could either stop the Cas9 piece of bacteria or even kill the genome edited repair. 

I think genome editing complements what can be done with gene therapy.- Dr. Matthew Porteus

Porteus said it all warrants more study to get a handle on it before medical researchers advance their CRISPR-Cas 9 work to try to treat patients. 

"I think genome editing complements what can be done with gene therapy," he said.

Part of the concern is that the field of gene therapy faced a major setback in 1999. A U.S. teen experienced a severe immune reaction to a gene delivery vehicle that was meant to correct his metabolic disorder. He died after receiving the injection.

Search for alternatives

At his lab, Porteus is developing gene corrections for diseases such as sickle cell anemia and severe combined immunodefiency or SCID, also known as bubble boy disease. 

Scientists are already starting to look for alternative sources for bacterial Cas9s. This study should motivate them to look for systems in bacteria that don't infect humans, Porteus said. 

Another possibility is to engineer the current Cas9 so it's not recognized by our immune system. 

Or there could be other ways to deliver Cas9 by suppressing the immune system for a time to prevent a reaction. This would need to be tested in animals before people.

As a pediatrician, Porteus said it's also possible that cellular and humoral immunity doesn't develop into adulthood. If so, the current Cas9 system might be useful for infants and children.