CRISPR (short for Clustered Regularly Interspaced Short Palindromic Repeats) — the genetic equivalent of a word processor — has received its most powerful upgrade yet: the ability to insert an entire gene at the most potentially effective spot, according to an article in the journal Science.
This marks a key step in cell and gene therapy, all of which aim to treat illnesses by making corrections or additions to the “misspelled” genes that can lead to disease.
Before CRISPR, delivering genes inside of neutered viruses was thought to be the answer. It sometimes worked, but often the new genetic word would be flooded into the body, inserted at random. Sometimes it would land in the right spot, other times it would miss its target. And worst of all, that approach can lead to a potentially deadly immune response.
The Rise of CRISPR
When CRISPR debuted in 2012, it was thought to provide both more specificity and control. It is essentially the genetic equivalent of a “search and replace” command in a word processor, with the ability to find, then snip out faulty DNA within one gene, using what many researchers call “molecular scissors.” Its innovators were awarded the Nobel Prize in Chemistry in 2020.
However, despite incredible potential, that approach still has some limitations. The “scissors” can sometimes snip the wrong part of the targeted DNA sequence. This could lead to either incomplete repair or the inadvertent admission of a harmful mutation. It can also only fix one error in a single gene at a time.
Despite those “software bugs” and limitations, early versions of CRISPR have shown promise. The approach was used to edit genes in six patients with a rare genetic disorder in 2022. More recently, scientists used the system to deliver for the first time a treatment tailored to a specific patient, a baby boy with a rare metabolic disorder.
Read More: CRISPR Gene-Editing Technology Enters the Body — and Space
CRISPR Upgrades
The multiple components of the evoCAST gene editor grasping a strand of DNA (red). (Image Cred: George Lampe (Columbia University Irving Medical Center))
The new version shows promise to be even more effective. Since it doesn’t cut out any existing DNA, it is less likely to inadvertently add mutations or errors. It is much more specific than either virus-based gene therapy or earlier CRISPR approaches. And delivering an entire correct gene is considered a safer, more effective approach than cutting and replacing portions of an existing one.
The update essentially involves the addition of guide molecules called “CRISPR-associated transposases (CASTs).” These bacterial systems “lead” CRISPR to specific sites, so the correct gene is more likely to be integrated and activated. The tool’s developers named it “evoCAST.”
Also, existing gene therapy strategies, as well as the early CRISPR work in humans, were focused on diseases with errors in only one gene. Although there are many such diseases, each one affects relatively few people, compared to more common diseases that are thought to be the result of multiple genetic mutations.
“Hundreds to thousands of different mutations in the CFTR gene can cause cystic fibrosis, for example, so an inordinate number of distinct gene editing drugs would be needed to ensure each patient could be treated,” Samuel Sternberg, a researcher at Columbia University and an author of the paper, said in a press release. “Instead, something like evoCAST could enable a single gene therapy that inserts a complete and healthy gene into the patient’s genome.”
CRISPR’s Future
The researchers will continue to test the evoCAST system in animals modelled to exhibit certain human diseases. As they do so, they intend to tweak and debug the system so it can be even more accurate and effective. But their biggest challenge is the same one that faced early gene therapy researchers: targeted delivery.
“How do we actually get these tools and their payloads into the cells or tissues of interest?” Sternberg said in a press release. “That’s a challenge that many of us in the field are facing.”
This article is not offering medical advice and should be used for informational purposes only.
Read More: CRISPR Fulfills Its Promise with First-Ever Personalized Gene-Editing Therapy
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Before joining Discover Magazine, Paul Smaglik spent over 20 years as a science journalist, specializing in U.S. life science policy and global scientific career issues. He began his career in newspapers, but switched to scientific magazines. His work has appeared in publications including Science News, Science, Nature, and Scientific American.
