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In clinical trial, injection improves vision in a form of childhood blindness


During the trial, a patient gained vision, which lasted more than a year, after a single injection of an experimental RNA therapy into the eye.

During a clinical trial, investigators at the Scheie Eye Institute in the Perelman School of Medicine at the University of Pennsylvania treated a Penn Medicine patient with a genetic form of childhood blindness with a single injection of an experimental RNA therapy into the eye.

The patient gained vision, which lasted more than a year, according to a release from Penn. Results of the case show that the treatment led to marked changes at the fovea, the most important locus of human central vision.1

According to investigators, the treatment was designed for patients diagnosed with Leber congenital amaurosis (LCA) — an eye disorder that primarily affects the retina—who have a CEP290 mutation, which is one of the more commonly implicated genes in patients with the disease. The investigators noted that patients with this form of LCA suffer from severe visual impairment, typically beginning in infancy.

Co-lead author Artur V. Cideciyan, PhD, a research professor of ophthalmology at the University of Pennsylvania, explained that the results set a new standard of what biological improvements are possible with antisense oligonucleotide therapy in LCA caused by CEP290 mutations.

“Importantly, we established a comparator for currently-ongoing gene editing therapies for the same disease, which will allow comparison of the relative merits of two different interventions,” he said in a statement.

Cideciyan and Samuel G. Jacobson, MD, PhD, a professor of ophthalmology led an international clinical trial led at Penn Medicine. In that trial, participants received an intraocular injection of an antisense oligonucleotide called sepofarsen. The investigators noted that this short RNA molecule works by increasing normal CEP290 protein levels in the eye’s photoreceptors and improving retinal function under day vision conditions.

Cideciyan, Jacobson, and collaborators, in a 2019 study, found that injections of sepofarsen repeated every three months resulted in continued vision gains in 10 patients. The 11th patient, whose treatment was detailed in the latest paper, received only one injection and was examined over a 15-month period.

Before the treatment, the investigators noted the patient had small vision fields, reduced visual acuity and no night vision. After the initial dose, the patient had decided not to receive the quarterly maintenance doses because regular dosing could result in cataracts.

According to investigators, prior to treatment, the patient had reduced visual acuity, small visual fields, and no night vision. After the initial dose, the patient decided to forgo the quarterly maintenance doses, because the regular dosing could lead to cataracts.

After the patient’s single injection of sepofarsen, more than a dozen measurements of visual function and retinal structure showed improvements supporting a biological effect from the treatment.

According to investigators, the trial showed that this biological effect was relatively slow in uptake. They saw vision improvement after one month, but the patient’s vision reached a peak effect after the second month. Most striking, the improvements remained when tested over 15 months after the first and only injection.

The investigators noted that the extended durability of vision improvement was unexpected and provides implications for treating other ciliopathies — the name of the large category of diseases associated with genetic mutations encoding defective proteins, which results in the abnormal function of cilia, a protruding sensory organelle found on cells.

Jacobson noted that the work represents a new direction for RNA antisense therapy.

“It has been 30 years since there were new drugs using RNA antisense oligonucleotides, even though everybody realized that there was great promise for these treatments,” he said in a statement. “The unexpected stability of the ciliary transition zone noted in the patient prompts reconsideration of dosing schedules for sepofarsen, as well as other cilium-targeted therapies.”

The investigators found that one reason why antisense oligonucleotide has proven successful in treating this rare disease is that these tiny RNA molecules are small enough to get into the cell nucleus, but are not cleared very quickly, so they remain long enough to do their work.

“There are now, at least in the eye field, a series of clinical trials using antisense oligonucleotides for different genetic defects spawned by the success of the work in CEP290-associated LCA from Drs. Cideciyan and Jacobson,” Joan O’Brien, MD, chair of ophthalmology in the Perelman School of Medicine and director of the Scheie Eye Institute, said in a statement.

Going forward, the Penn investigators are planning gene-specific therapies for other currently incurable blinding inherited retinal disorders. The trial is being funded by ProQR Therapeutics with additional support from the National Institutes of Health.


Artur V. Cideciyan, Phd, et. al. Durable vision improvement after a single treatment with antisense oligonucleotide sepofarsen: a case report. Published April 1, 2021. Nature Medicine. https://www.nature.com/articles/s41591-021-01297-7

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