Expanding Tunnel Vision

Scheie Eye Institute researchers have shown that a single intraocular injection of antisense oligonucleotide (ASO) sepofarsen can lead to marked changes at the fovea in Leber congenital amaurosis (LCA) patients with the common CEP290 mutation (1). In a clinical trial, 11 participants received an injection of the short RNA molecule (which increases CEP290 protein levels in the eye’s photoreceptors to improve retinal function). Ten of the participants were re-injected at intervals of three months. The current report is on the eleventh patient with reduced visual acuity, tunnel vision, and no night vision who received just a single dose. The researchers found substantial visual improvements, including expansion of the visual field, that were retained for more than 15 months.

“These improvements followed similar time courses [to the 10 other patients], peaking near three months post-injection, and many measures remained better than baseline at 15 months” explains Artur V. Cideciyan, Research Professor of Ophthalmology, and lead author of the study. “The extended durability was very surprising considering that sepofarsen half-life in the retina had been previously estimated to be around two months. Different measures allowed us to locate the distribution of the improvements in the immediate foveal region. However, further from here, improvements did not match predictions, suggesting that ASO access to photoreceptors in extrafoveal regions with thicker retina may be more limited.”

Why was the biological effect relatively slow to appear? Cideciyan hypothesised the delay could depend on diffusion and translocation of the ASO across the vitreous and retina into the foveal cone photoreceptor nucleus, and on synthesis of additional normal CEP290 mRNA and protein – “but it is likely that these steps occur in a matter of hours or days so they do not fully explain the ‘why’” he says. The team are now evaluating whether previously uninjected contralateral eyes demonstrate similar efficacy in an ongoing extension trial with nine of the original 11 study participants. They hope that, by better understanding the effect’s durability, they can establish an appropriate frequency for future maintenance injections.