The genome editing technology CRISPR has evolved from the darling of research labs around the world — enabling new types of experiments in a much more efficient way — to the great hope for unlocking cures for inherited diseases.
But as scientists ready CRISPR-based therapies for clinical trials, how can they reduce the chances that they might edit parts of the genome that weren’t targeted? And how can they get CRISPR editing complexes to the targeted cells to make the necessary fixes to treat or cure a disease?
“It’s all well and good that we can do this genome editing in Petri dishes in the lab,” said Nicole Gaudelli, a senior scientist and program leader at Beam Therapeutics. But, she pointed out, it can be much more difficult to ferry CRISPR into the lungs or liver.
Gaudelli and other CRISPR experts discussed those challenges — as well as their core optimism for the future of CRISPR — at a panel Tuesday morning as part of HUBweek, the annual “festival for the future” founded by The Boston Globe, Harvard University, Massachusetts General Hospital, and the Massachusetts Institute of Technology.
Even as the panelists outlined the potential problems that could trip up CRISPR-based treatments, they emphasized that many of them had already been solved or were in the process of being figured out as new technologies were honed.
Dr. Vikram Pattanayak, an assistant in pathology at Mass. General and a panelist, studies off-target effects — essentially, what CRISPR does to the genome at spots you weren’t meaning to hit. But he noted that pairing CRISPR with Cas9, the main enzyme researchers have used with CRISPR over the years, was already quite precise, and that a few small tweaks to the workhorse enzyme made the system even more accurate.
“It’s specific enough that you can target what you want without hitting most of what you don’t want,” Pattanayak said.
Even if concerns about off-target effects are addressed, there could be other challenges with using CRISPR in the clinic.
Some research has suggested that many people have a preexisting immunity to Cas9, which could render it ineffective. Other enzymes may be easier to deliver to certain organs.
By surveying the landscape of enzymes now, scientists can ensure that clinical applications of CRISPR don’t run into any unexpected enzyme-related roadblocks, said Erik Sontheimer of the University of Massachusetts Medical School.
“You can go to the shelf and pull out the Cas9 or Cas12 or whatever enzyme you want,” said Sontheimer, who is also a co-founder of Intellia Therapeutics.
Gaudelli also highlighted the ways in which “base editing” could help avoid the genetic chaos that might be unleashed by other forms of CRISPR editing. In base editing, scientists don’t need to cut the genome to operate; rather, CRISPR simply swaps one DNA “letter,” or base, for another, like a G to an A. The vast majority of inherited diseases are the result of such simple genetic typos.
“If we could just change that misspelling back to what it’s supposed to be … we could in theory fix that,” she said.
One audience member asked if the clinical deployment of CRISPR might surface problems that simply couldn’t be foreseen in existing lab studies. What if editing one gene might have some secondary consequence for another gene that existing models couldn’t demonstrate, for example?
Panelists pointed out that the point of current CRISPR aims was to revert disease-causing genetic variants into healthy variants that most people already have. It is not as if clinicians are hoping to conjure up some never-seen-before genetic combinations.
Plus, the panelists said, the first patients to undergo CRISPR treatments have conditions that haven’t been well-managed by other approaches.
“For those people who are in clinical trials, for those people who receive this clinically, somebody would have made the determination that there were far more risks to not getting the treatment than risks to getting the treatment,” Pattanayak said.
STAT senior science writer Sharon Begley, who moderated the session, also asked the panelists if there were some genetic diseases that might be so complicated or some organ systems that are so hard to reach that a CRISPR approach might not ever exist. They acknowledged that switching off cancer-driving genes in tumors was beyond what experts can do now, but they pointed out that CRISPR is already being used to develop the next generation of immunotherapies. Overall, they said, they didn’t want to underestimate CRISPR.
“I usually prefer not to predict impossibility,” Sontheimer said.