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CHOP-Penn Team Tests First In-Body CRISPR Therapy to Treat Blindness

Published on June 20, 2024 in Cornerstone Blog · Last updated 3 weeks 1 day ago


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Jacob Peckham
Jacob Peckham, now 12, was born with an inherited form of retinal blindness. He was among two children to receive an experimental gene-editing therapy at CHOP.

By Lauren Ingeno

Using CRISPR/Cas9 gene editing — the Nobel Prize-winning technology that cuts and modifies DNA with pinpoint accuracy — researchers from Children’s Hospital of Philadelphia and the University of Pennsylvania’s Scheie Eye Institute improved vision in two children with a severe inherited form of retinal blindness, who participated in an early-phase, multi-institutional clinical trial.

The phase 1/2 BRILLIANCE clinical trial included the two children (ages 10 and 14) and 12 adults at five sites across the country. The participants were born with a form of the retinal disease Leber Congenital Amaurosis (LCA) that is caused by mutations in the CEP290 gene.

The findings, published in the New England Journal of Medicine, showed that the experimental gene-editing treatment (EDIT-101, Editas Medicine and Allergan) was safe and improved sight in half of the patients who received it.

“This is groundbreaking in many ways,” said Tomas S. Aleman, MD, a CHOP ophthalmologist and professor at the University of Pennsylvania, who served as a site principal investigator, co-lead for the study analyses, and study co-corresponding author. “It’s the second time gene-editing has been used to treat a disease in humans, and the first time it’s been used to safely and successfully treat an eye disease.”

CEP290-associated inherited retinal degeneration (CEP290-IRD), the most common and severe LCA subtype, causes dysfunction and death of the retina’s light-sensitive photoreceptor cells. This leads to vision loss within the first decade of life.

“It’s difficult to treat because there is a relatively small window before vision is lost completely,” Dr. Aleman said. “In the absolute best case, a patient will be able to read the largest letter on a visual acuity test. In most cases, it’s much worse.”

Though there is currently no treatment for the disease, patients often have an intact layer of dysfunctional cone photoreceptor cells in their macula, the part of the retina that controls central vision. This gave scientists a clue that there may be an opportunity to intervene by targeting spared photoreceptors to restore vision.

Gene Editing Versus Gene Therapy

The gene therapy voretigene neparvovec-rzyl (Luxturna™, Spark Therapeutics), which was developed at CHOP/Penn, uses an adeno-associated virus (AAV) vector to treat a form of LCA. The vector, which is injected into the eye, delivers a correct copy of the affected gene (RPE65) to retinal pigment cells.

By contrast, the CEP290 gene that is dysfunctional in CEP290-IRD is much too large to be packaged inside of an AAV. To overcome this limitation, scientists behind the development of EDIT-101 created a therapy that corrects the gene mutation using genome editing.

Rather than carrying a correct copy of the affected gene, the AAV vector used in the EDIT-101 therapy contains two “guide” RNA molecules and a Cas9 protein. Once injected into the eye, the guide RNA directs the Cas9 protein to the affected gene, which performs the necessary cut to the DNA and makes it functional.

Earlier this year, the U.S. Food and Drug Administration approved a treatment that uses gene-editing to treat sickle cell disease. Bone marrow cells are extracted from the body, corrected with CRISPR, and then transplanted back into the patient.

EDIT-101 works differently: The snipping and re-arranging takes place insideof the body. This approach comes with a few advantages, including reducing the risks of side effects and rejection that come with transplantation.

For Dr. Aleman, the results of the CRISPR/Cas9 gene-editing study are enough evidence to move the therapy forward to its next clinical trial stages. He also hopes the therapy will eventually be tested in children under 2 years old.

“There is a window of opportunity in kids, not only in the sense that you will prevent progression, but that you will impact the development of connections between the eye and brain. The window is not that wide,” Dr. Aleman said. “When a treatment like this is efficacious, I think it’s important to take the positives and test it in the population for which it will have the biggest impact.”