From left to right: Samuel G. Jacobson, MD, PhD, Artur V. Cideciyan, PhD
By Rebecca Salowe
Scheie Vision Annual Report 2021
In a recent publication in Nature Medicine, Scheie researchers showed that a patient with a genetic form of childhood blindness gained vision that lasted for more than one year after receiving a single injection of an experimental RNA therapy. This study was led by Artur V. Cideciyan, PhD and Samuel G. Jacobson, MD, PhD, Professors of Ophthalmology and co-Directors of the Center for Hereditary Retinal Degenerations.
The patient was a participant of a larger international clinical trial for patients with Leber congenital amaurosis due to a CEP290 mutation, which is a commonly implicated genetic cause for this disease. Patients with this mutation typically have severe visual impairment that begins in infancy.
Patients in the clinical trial received an intravitreal injection of an antisense oligonucleotide called sepofarsen. This short RNA molecule is designed to correct the commonly occurring CEP290 mutation. A prior study, also led by Drs. Cideciyan and Jacobson and published in Nature Medicine, showed that repeated injections of sepofarsen every three months resulted in consistent vision gains in 10 patients.
The 11th patient—featured in this most recent publication—received only one injection of sepofarsen. The patient decided to forgo the quarterly maintenance doses to avoid potential adverse effects, but allowed for continued monitoring.
“Sepofarsen half-life within the non-foveal retina was previously estimated to be two months based on animal studies,” said Dr. Cideciyan. “Our work showed that this second-generation antisense oligonucleotide remains active in human foveal cone photoreceptors for more than 15 months and continues to provide improved vision throughout this period.”
Before treatment, the patient had reduced visual acuity, limited visual fields, and no night vision. Fifteen months after the single injection, the patient maintained large improvements in vision, which were characterized by more than a dozen measurements of visual function and retinal structure.
“Peak vision improvement occurred near three months after the injection,” explained Dr. Cideciyan. “Most impressive were co-occurrence of subjective measures, such as acuity and visual fields, with objective changes, such as pupil responses and retinal structural improvements, confirming without a doubt the biological effect in foveal cones.”
The durability of effect is believed to be a result of increased levels of normal CEP290 protein, as well as the slow natural rate of degradation of this protein. The molecule is small enough to enter the cell nucleus, but is not cleared away quickly, so it remains effective for a long duration.
“This work represents an exciting direction for RNA antisense therapy,” said Dr. Jacobson. “The unexpected stability of vision improvements noted in the patient prompts reconsideration of dosing schedules for sepofarsen, as well as other cilium-targeted therapies directed to the fovea.”
Additionally, antisense oligonucleotide therapy has the potential to treat many other monogenic diseases. In ophthalmology, a number of clinical trials using antisense oligonucleotides for genetic defects are now in progress. Gene editing is another promising approach in this area, and the relative merits of each intervention for different diseases and patients can now be compared.
The research team included Wills Eye Hospital surgeon Allen C. Ho, MD, and Scheie researchers Alexandra V. Garafalo, Alejandro J. Roman, Alexander Sumaroka, Arun K. Krishnan, and Malgorzata Swider.
References
Cideciyan AV, Jacobson SG, Ho AC, et al. Durable vision improvement after a single treatment with antisense oligonucleotide sepofarsen: a case report. Nat Med. 2021;27:785–789.
Cideciyan AV, Jacobson SG, Drack AV, et al. Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect. Nat Med. 2019;25(2):225-228.