A patient with a genetic form of blindness in children developed vision that lasted for more than a year after receiving experimental RNA therapy in the eye.
The gene editing research was done at the Perelman School of Medicine at the University of Pennsylvania. Results of the case, set out in a paper published on 1 April in Physical Medicine, shows that the treatment led to noticeable changes to the fovea, the most important point of man’s central vision.
In the international clinical trial, participants received an intraocular injection of an antisense oligonucleotide called sepofarsen. This short RNA molecule works by increasing normal CEP290 protein levels in the photoreceptors of the eye and improving retinal function under day vision conditions.
The treatment is designed for patients diagnosed with Liver congenital amaurosis (LCA) – an eye disorder that mainly affects the retina – that has a CEP290 mutation, which is one of the more common genes in patients with the disease. Patients with this form of LCA suffer from severe visual impairment, which usually begins in infancy.
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“Our results set a new standard of biological improvement that is possible,” said co-lead author Artur Cideciyan, PhD, a research professor of ophthalmology at the Scheie Eye Institute of Penn Medicine. “What is important is that we have set up a comparator for current gene-editing therapies for the same disease, which can compare the relative benefits of two different interventions.”
In a study published in 2019 in Nature Medicine, Cideciyan and collaborators, including dr. Samuel G. Jacobson, found that injections of sepofarsen repeated every three months resulted in continued vision increase in 10 patients.
The eleventh patient, whose treatment was outlined in the latest article, received only one injection and was examined over a period of 15 months. Prior to treatment, the patient had reduced visual acuity, small fields of vision and no night vision. After the initial dose, the patient decided to discontinue the quarterly maintenance doses, as the regular dose may lead to cataracts.
Great improvement in a ‘microdose’
After a single injection of sepofarsen, more than a dozen measurements of visual function and retinal structure showed major improvements supporting a biological effect of the treatment. An important finding from the case was that this biological effect was relatively slow. The researchers saw vision improvement after one month, but the patient’s vision reached a peak after month two. Most notably, the improvements remained when tested more than 15 months after the first and only injection.
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According to the researchers, the long-term improvement in visual acuity was unexpected and had implications for the treatment of other siliopathies – the name of the large category of diseases associated with genetic mutations encoding defective proteins, leading to the abnormal function of cilia, an outstanding sensory organelle. found on cells.
‘This work is a very exciting direction for RNA antisense therapy. ‘There were thirty years ago that there were new drugs with RNA antisense oligonucleotides, although everyone realized that there was a big promise for these treatments,’ Jacobson said. “The unexpected stability of the ciliary transition zone observed in the patient calls for a reconsideration of the dosing schedules for sepofarses, as well as other cilium-targeted therapies.”
According to the researchers, one of the reasons why antisense oligonucleotide is successful in treating this rare disease, is that these small RNA molecules are small enough to get into the cell nucleus, but that they are not cleaned very quickly, so stay tuned them long enough for their work.
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For future studies, the Penn authors plan no-specific therapies for other currently incurable blinding hereditary retinal disorders.
Source: Penn Medicine
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