For the first time, doctors have injected a person with a treatment that will rely on CRISPR gene-editing to treat blindness.
The milestone comes as part of an ongoing clinical trial to evaluate whether the treatment is safe and effective for people with a specific mutation in a single gene; in this case, one that leads to eye disease and vision loss.
CRISPR is a gene-editing tool adapted from the antiviral defense systems of bacteria that can precisely target and cut out short sequences of DNA from longer strands. The technique is being used in ongoing trials to treat cancer and sickle cell anemia by editing human cells outside the body and injecting them into a patient once they’ve been CRISPR’d; however, this blindness trial is the first that delivers the gene-editing treatment directly into a person’s body, NPR reported—specifically, their eye.
The person was treated at the Oregon Health & Science University Casey Eye Institute in Portland, but investigators reached for comment would not provide further information about the patient or effects of the treatment. The trial is a collaboration between genome-editing company Editas Medicine, pharmaceutical company Allergan, and four participating eye centers.
“This marks a new era in medicine where we can test tools to access and treat the root cause of a genetic disease inside a person's body,” said Jason Comander, a co-investigator of the trial and the associate director of the Inherited Retinal Disorders Service at Massachusetts Eye and Ear.
Comander said that Eric Pierce, the principal investigator of the trial, pitched Editas the idea of a CRISPR-based therapy for this particular eye disease several years ago. The first patient was enrolled in the trial in September 2019.
People enrolled in the trial must have a mutation in CEP290, a gene that makes an important protein in cell structures. They must also have a visual acuity of light perception of at most 20/50. While this is higher than the legally blind standard of 20/200 visual acuity, Comander said that most of the enrolled patients are considered legally blind, and those who are not have other significant deficits in their vision.
Both the organ and mutation targeted are ideal for a first test of in-body CRISPR, Comander said. The eye is small and isolated from the rest of the body, so doctors only have to inject a small amount of virus, which is harmless but contains CRISPR machinery. It’s also easy to gauge the effects of any treatment on the eye. Moreover, the specific mutation in CEP290 is “more forgiving” than other mutations that cause congenital diseases, Comander said.
A human gene is a bit like the first draft of a book before it gets sent to an editor. Before protein-making machinery can read the gene, some DNA sequences need to be spliced out. These sequences are called introns, while the chapters that make the cut for the book are called exons.
“This particular mutation causes an error in the way that those exons, or book chapters, are put together, so it causes inclusion of a stretch of DNA that shouldn't be in the final product,” Comander said. “When we clip out that portion of the DNA, then that extra chapter doesn't get included anymore.”
The mutation itself is a single base pair substitution—a G instead of an A—but since it occurs in an intron, you can cut out a larger region and still repair the gene.
Comander and Pierce have worked on another gene-therapy eye treatment called Luxturna. The CEP290 gene is too large for the technique that Luxturna relies on to deliver edited DNA into the retina, and there are no other available therapies besides CRISPR to treat the eye diseases caused by the mutation.
“Without this approach, we would have nothing to offer these patients,” Comander said, likening the technique to taking a toolbox into the retina itself.
Surgeons at eye centers in Oregon, Michigan, Florida, and Massachusetts will treat up to 18 people as part of the trial; Comander will perform the surgery at Massachusetts Eye and Ear. In the case of the Oregon patients, as well as in future surgeries, the patient is put under general anesthesia, and surgeons drill tiny holes into the white of one eye. They then deposit three drops of liquid containing hundreds of billions of copies of a virus under the retina.
Patients’ eyes and vision will be monitored for a year after surgery. If the trial shows that this kind of in-body CRISPR therapy is safe and effective, Comander said that there could be many other diseases throughout the body that this technique could treat or cure.
“If we can fix the underlying genetic defect, we have the potential to restore vision, or even produce vision in a patient who's never had reasonable vision before,” he said. “It does take a long time to turn a tool into a medicine, and years of development by Editas were required before the concept can be tested in people, and it's very exciting that we're at the point where we're able to try it now.”