While Leber congenital amaurosis (LCA) may not have the name recognition of congenital disorders, it does represent one of the most common causes of blindness in children. Now, investigators at the Scheie Eye Institute in the Perelman School of Medicine at the University of Pennsylvania (UPenn) have just published exciting new data showing the success of a new therapy that improved the vision of LCA affected children in a small clinical study. Findings from the new study were published recently in Nature Medicine, in an article titled, “Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect.”

“It was very dramatic to see one of the patients improve from only being able to differentiate light or dark to reading many letters on an eye chart at two months following the first injection,” noted lead study investigator Artur Cideciyan, Ph.D., a research professor of ophthalmology at UPenn. “So, we performed a thorough interim analysis of all results from all patients.”

The treatment was designed for patients with CEP290 mutations and a diagnosis of LCA. CEP290 acts as a gate between two compartments of photoreceptor cells—a type of sensory neuron in the retina that converts light into signals that provide vision. Primary photoreceptor blindnesses—such as those caused by CEP290 mutations—are the most common form of LCA and they are currently not treatable.

In this clinical study at sites in the U.S. and Europe, participants received an intraocular injection of an oligonucleotide—a short RNA molecule—created to reduce the mutant CEP290 protein levels in the photoreceptors and restore retinal function.

Ten patients received at least one injection into their worst-seeing eye. At three months after the first injection, half of the patients showed improvements in visual acuity, measured by the ability to either read letters or distinguish the direction of black and white bars.

The most basic functions of photoreceptors are to receive and then signal light. This aspect of vision was tested in patients by presenting flashes of light in the dark and measuring the dimmest flash intensity detected. Treated eyes could detect on average more than six-fold dimmer lights three months after the injections compared to before. The results were highly statistically significant. Evaluations with two colors of flashes suggested that it was the cone photoreceptors used for daytime vision that were improving with the treatment.

“This therapy to repair the genetic defect in LCA10 is a breakthrough in treatment strategy and will open the door for clinical trials in other patients with this condition and other similar conditions that are currently untreatable,” remarked co-lead study investigator Samuel Jacobson, M.D., Ph.D., a professor of ophthalmology at UPenn.

All patients enrolled so far into the study had two different CEP290 mutations. The p.Cys998X mutation causing a splicing defect was common in all patients and was specifically targeted by the oligonucleotide.

“We performed an extreme form of personalized medicine where we targeted not just a specific gene but a specific mutation in a gene,” Dr. Cideciyan concluded. “It is gratifying to see clinical evidence supporting the action of this oligo predicted from basic science. In the future, we hope to evaluate patients carrying two identical splicing mutations to determine whether the efficacy of the injection might be even greater.”