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Drs. Jacobson and Cideciyan
Samuel Jacobson, MD, PhD (left) and Artur Cidecyian, PhD (right).
By Rebecca Salowe
Scheie Vision Summer 2019

Researchers at the Scheie Eye Institute recently showed visual improvement in patients with a rare form of congenital retinal blindness. Artur Cideciyan, PhD, and Samuel Jacobson, MD, PhD, co-investigators on this study, published these results in Nature Medicine.

The treatment was designed for patients with a specific form of Leber Congenital Amaurosis (LCA), which is a childhood blindness that leads to severe vision loss. This form of disease (LCA10) is caused by mutations in the CEP290 gene.  The defect typically leads to loss of all rod photoreceptors, but cone photoreceptors are preserved for many decades, creating a large window for possible interventions to improve their function. 

Drs. Cideciyan and Jacobson used an oligonucleotide (short RNA molecule) to decrease mutant CEP290 protein levels.  This oligonucleotide was designed to correct pre-mRNA splicing, preventing translation of a premature truncation codon (which leads to a nonfunctional protein product). This process would reduce mutant CEP290 protein levels and hopefully restore retinal function.

The research team conducted a Phase 1/2 clinical trial to assess the safety and tolerability of this oligonucleotide (called QR-110) in patients with LCA due to a CEP290 mutation. Five patients received intravitreal injections of the oligonucleotide into their worse-seeing eye by Dr. Allen Ho, a long-standing collaborator from the Wills Eye Hospital.  Six additional patients were injected in the US and Europe.  The researchers then intended to compare vision in the treated and untreated eyes.

However, after seeing dramatic results from one of Dr. Jacobson’s patients after only two months, the sponsor decided to conduct an interim analysis of all patients.  This particular patient went from only being able to differentiate light and darkness, to reading multiple letters on an eye chart.  

The interim analysis showed that three months after the first injection, 50% of patients had significant improvements in visual acuity and detection of dimmer flashes.  Further investigation with two colors of flashes suggested that cone photoreceptors (used for daytime color vision) were improving with treatment.  

“It was enormously gratifying to see robust improvements in visual acuity and significant increases in the patient’s ability to detect lights, and impressive to observe these effects within the first three months following a single injection,” said Dr. Cideciyan.

The trial, funded by ProQR Therapeutics, is still in progress and is a multi-center effort involving groups in the US and in Europe.  Researchers will continue to measure the safety and efficacy of the injections long-term and the effects of further doses.  

“LCA10 is a severe form of childhood blindness and this is a major step forward in the treatment of these previously incurable conditions,” said Dr. Jacobson.
The therapy may even have applications for other retinal diseases.  “This work opens the door to evaluating similar approaches in other inherited retinal degenerations where antisense gene therapy can modulate proteins in photoreceptors in order to improve vision or slow down progressive degeneration or both,” said Dr. Cideciyan. 



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