Early Gene Therapy Trials for Retina Disorder Yield Promise


University of Pennsylvania investigators conducted an interim analysis of a year-long study on intraocular injections of a mutation-specific gene therapy when one patient showed dramatic early improvements.

Artur V. Cideciyan, PhD

Artur V. Cideciyan, PhD

A new intraocular injection gene therapy, QR-110, may be able to treat Leber congenital amaurosis (LCA) caused by a specific CEP290 mutation, according to early results of an ongoing phase 1/2 trial.

Lead author Artur V. Cideciyan, PhD, research professor of Ophthalmology at the University of Pennsylvania, told MD Magazine® the preliminary findings come in the era of personalized medicines—particularly highlighted by the introduction of therapies for monogenic conditions like retinal degeneration.

“Our current work takes this gene-specific personalized medicine for inherited retinal disease one step further by making the treatment mutation-specific,” Cideciyan said. “Our positive results show for the first time that intraocularly-injected anti-sense oligos can improve vision by modulating aberrant splicing.”

The team, which has been studying inherited retinal degeneration for decades, decided to conduct an interim analysis of their study when they saw particularly dramatic results from one of the patients. Cideciyan noted a patient improved from only being able to differentiate light or dark at baseline, to reading multiple letters on an eye chart at 2 months-post first injection.

The trial of QR-110, developed by ProQR Therapeutics, is ongoing and designed to last 1 year. Ten patients aged 6 or older are receiving intraocular injections of the drug in their worse-seeing eye once every 3 months for a year. Vision in this eye is then compared to that of the untreated eye.

The most common CEP290 mutation is a single nucleotide change in intron 26 that reduces the amount of CEP290 protein. Low levels of this protein prevent patients’ photoreceptors from sensing light. QR-110 is an anti-sense oligonucleotide which is believed to block recognition of this mutation, and thus increase the amount of functional CEP290, improving patients’ eyesight.

Four of the participants had had their first injection 6 months prior to the interim analysis, and another 4 had had theirs 3 months prior. The team found no safety concerns—no adverse events and no intraocular inflammation.

At each visit, the researchers tested patients’ best-corrected visual acuity (BCVA) in both the treated and untreated eyes. One month after treatment, they found no changes, but after three months, the one patient saw a large improvement (2.7 log10 MAR), while 4 other patients had smaller, but still clinically significant, improvements. For those patients who had data up to six months, the improvements over baseline were retained.

The study is expected to conclude at the end of this year.

“This work opens the door to evaluating similar approaches in other inherited retinal degenerations where antisense gene therapy can modulate protein content in photoreceptors in order to improve vision or slow down progressive degeneration or both,” said Cideciyan.

The study, "Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect," was published online in the journal Nature.

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