Illustration: Sarah Grillo/Axios

A gene editing tool with promising clinical applications is facing renewed scrutiny after several recent studies found its side effects could be worse than expected.

Sometimes heralded as "revolutionary," CRISPR-Cas9 is the subject of a massive investment of money and research efforts toward the ultimate goal of editing human genes, which many hope will begin on a trial basis in the U.S. this year.

The big question: Is CRISPR-Cas9 safe enough to expand it into human clinical trials? The consensus of scientists whom Axios spoke with: Not quite yet.

"The CRISPR reagents are wonderful tools for research but we still do not control them enough for safe and efficient use into patients. Particularly we know very little about the DNA repairing mechanisms triggered after the cut by Cas9."
— Lluis Montoliu, research scientist, Spanish National Research Council (CSIS)

CRISPR is a hot topic, and for good reason: it could have a wide range of applications for treating diseases and correcting genetic conditions in humans.

What's happening: Yesterday Science Translational Medicine published a study in which researchers took cancer cells that had left their original tumor in mice, edited them with CRISPR to have "suicide genes," and re-injected them into the animal to see if they would return to the tumor and end up killing the cancer. They found "marked survival benefits."

  • NIH Director Francis Collins told STAT in an early May interview:
"I’m very excited about the potential of gene-editing to cure rare diseases for which we know the molecular defect and there’s no current therapy."

Research money is flowing into large and small companies aiming to be on top of the market. Axios' Bob Herman provided the chart below for a quick peek at three companies focused on CRISPR research.

Funding that three of the top CRISPR companies have raised since they were founded. Data from Crunchbase on July 18.

Still, there's always been a steady drumbeat of cautionary tales since it's been known the editing process often targets the wrong gene. Problems can also be caused when the cell repairs itself after the editing process, Montoliu says.

This was brought sharply into focus in recent studies:

  • Earlier this week, U.K. scientists published a study in Nature Biotechnology saying in some cases CRISPR may cause large deletions and rearrange the DNA it is targeting. They warned that the problem has been "seriously underestimated."
  • This follows recent studies that found CRISPR may inadvertently increase the risk of triggering cancer.
  • In May, the FDA halted a trial for sickle cell patients before it started. Scientists planned to edit bone marrow stem cells using CRISPR and then transplant them back into the patients.

There are other CRISPR programs, though, that may be less prone to errors, such as base editing that allows for one or a few specific base DNA pairs to be altered without the creation of a double-strand break, which is often when the cell repair function creates errors. 

Shondra Pruett-Miller, director of the Center for Advanced Genome Engineering at St. Jude Children’s Research Hospital, says base editing is relatively new and is limited to small modifications, but it shows promise. "The ability to make genome edits without creating potentially dangerous DNA double-strand breaks is a great idea and could potentially have reduced risks," she says.

What's next: Patrick Hsu, a principal investigator and Salk Helmsley fellow at the Salk Institute for Biological Studies, says there should be standardized protocols and data analysis pipelines for the field.

Michael Kosicki, study author of the Wellcome Sanger Institute study from the U.K., agrees more analysis is needed before clinical trials can proceed, even with base editing. He says:

"Some questions that need to be asked when attempting 'regular DSB' CRISPR therapy are: Is there any important genes close to the one we want to edit? How often do large deletions, rearrangements and especially translocations happen in relevant cells? And finally, how much risk is acceptable? The answer to the last question depends on how serious the treated disease is."

Still, there remains hope for the future use of CRISPR in humans. Once it's proven safe and effective, Pruett-Miller says children could especially benefit from CRISPR-Cas9 therapy.

"CRISPR-Cas9 therapies are especially exciting because they are not limited to one disease and have the potential to correct disease-causing mutations at the source (the genomic DNA).  The hope is that if we can correct these genomic mutations early in life, we could prevent the devastating effects associated with a lifetime of accumulating damage, which often results in shortened lifespans."
— Shondra Pruett-Miller

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