WHY THIS MATTERS IN BRIEF

Normally doctors correct faulty genes outside of the body, this is the first time ever it’s been done inside the body.

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A while ago I wrote about a patient with Hunter’s syndrome in the US who became the first person in the world to have his genome edited in vivo while he sat in a hospital bed on an IV drip so he could be cured of the horrible, fatal genetically inherited disease. And the treatment worked. Now though, in another world first a person with a genetic condition that causes blindness has become the first to receive an in vivo CRISPR gene therapy treatment that was administered directly into their body.

The treatment was part of a landmark clinical trial to test the ability of CRISPR, a revolutionary gene editing technique nicknamed the Genesis Engine, to remove genetic mutations that cause a rare condition called Leber’s Congenital Amaurosis 10 (LCA10). No treatment is currently available for the disease which is a leading cause of blindness in childhood and this made the trial even more important.

The trial explained

During the trial the components of the gene editing system, which were encoded in the genome of a virus, were injected directly into the patients eye near their photoreceptor cells, rather than into the genomes of cells in petri dishes that have been removed from the human body which up until now has been the only other way to perform this type of treatment before being infused back into the patient.

“It’s an exciting time,” says Mark Pennesi, a specialist in inherited retinal diseases at Oregon Health and Science University in Portland. Pennesi is collaborating with the pharmaceutical companies Editas Medicine of Cambridge, Massachusetts, and Allergan of Dublin to conduct the trial, which has been named BRILLIANCE, and which is the first trial to use the CRISPR technique to delete a genetic mutation in the gene CEP290 that is responsible for LCA10.

The condition is a particularly attractive target for this type of therapy because conventional gene therapies use a virus to insert a healthy copy of the mutated gene into affected cells, but CEP290 is too large to slip the entire gene into a viral genome, says Artur Cideciyan, who studies retinal diseases at the University of Pennsylvania in Philadelphia. And although mutations in CEP290 disable light-sensing cells called photoreceptors in the retina, the cells are still present and alive in people with LCA10.

“The hope is that you can reactivate those cells,” says Pennesi. “This is one of the few diseases where we think you could actually get an improvement in vision.”

Early results from another therapy suggest that this might be the case. Cideciyan has teamed up with ProQR of Leiden, the Netherlands, to treat people with LCA10 using an experimental treatment called Sepofarsen. Early results suggest that sepofarsen, which uses a technique called antisense therapy to correct an LCA10-causing mutation in RNA made from the CEP290 gene, can improve vision in people with LCA10.

“For now, the use of CRISPR in the body is a significant jump from treating cells in a dish,” says Fyodor Urnov, who studies genome editing at the University of California, Berkeley. “It is akin to space flight versus a regular plane trip,” he says. “The technical challenges, and inherent safety concerns, are much greater.”

Nature: 579, 185 (2020) 10.1038/d41586-020-00655-8