A patient with a genetic form of childhood blindness developed vision, which lasted for more than a year after receiving a single injection of experimental RNA therapy into the eye.
The gene editing study was conducted at the Perelman School of Medicine at the University of Pennsylvania. Results of the case, detailed in a paper published April 1 in Natural medicine, shows that the treatment leads to marked changes in the fovea, the most important point of human central vision.
In the international clinical trial, participants received an intraocular injection of an antisense oligonucleotide called sepophars. This short RNA molecule works by increasing normal CEP290 protein levels in the photoreceptors of the eyes and improving retinal function under day vision conditions.
The treatment is designed for patients diagnosed with Liver congenital amaurosis (LCA) – an eye disorder that primarily affects the retina – who have a CEP290 mutation, which is one of the most commonly implicated genes in patients with the disease. Patients with this form of LCA suffer from severe visual impairment, typically beginning in infancy.
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“Our results set a new standard of what biological improvements are possible,” said co-lead author Artur Cideciyan, PhD, a research professor of ophthalmology at Penn Medicine’s Schae Eye Institute. “Importantly, we set up a comparator for currently ongoing gene therapy therapies for the same disease, allowing comparisons to be made from the relative merits of two different interventions.”
In a 2019 study published in Nature Medicine, Cideciyan and collaborators, including Drs. Samuel G. Jacobson, found that repeated injections of sepocars resulted in sustained vision gain in 10 patients every three months.
The eleventh patient, whose treatment was detailed in the last paper, received only one injection and was examined over a period of 15 months. Prior to treatment, the patient had reduced visual acuity, small visual fields, and no night vision. After the initial dose, the patient decided to give up the quarterly maintenance doses, as the regular dose could lead to cataracts.
Great improvement in one ‘microdose’
After a single injection of sepsis, more than a dozen measurements of visual function and retinal structure showed major improvements that support a biological effect of the treatment. An important finding from the case was that this biological effect was relatively slow in uptake. The researchers saw improvement in vision after one month, but the patient’s vision reached a peak effect after peak two. Most striking were the improvements when they were tested for more than 15 months after the first and only injection.
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According to the researchers, the extended duration of vision improvement was unexpected and had consequences for the treatment of other ciliopathies – the name of the large category of diseases associated with genetic mutations that encode defective proteins, resulting in the abnormal function of cilia, a protruding sensory organelle found on cells.
“This work represents a really exciting direction for RNA antisense therapy. “It’s been 30 years since there were new drugs with RNA antisense oligonucleotides, although everyone is aware that there was great promise for these treatments,” Jacobson said. “The unexpected stability of the ciliary transition zone observed in the patient requires reconsideration of dosing plans for sepsis, as well as other cilium-targeted therapies.”
One reason why antisense oligonucleotide has proven successful in treating this rare disease is, according to the researchers, that these small RNA molecules are small enough to enter the cell nucleus, but are not cleared quickly, so they last long enough continue to do their job.
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For future studies, the Penn authors plan gene-specific therapies for other currently incurable blinding hereditary retinal disorders.
Source: Penn Medicine
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