A single injection reverses blindness in a patient with a rare genetic disorder: another RNA success


A patient with a genetic form of childhood blindness gained vision, which lasted more than a year, after receiving a single injection of an experimental RNA therapy into the eye.

Vanessa bumbeers

The gene editing research was carried out at the Perelman School of Medicine at the University of Pennsylvania. Results of the case, detailed in an article published on April 1 in Nature medicine, show that the treatment caused 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 sepofarsen. This small RNA molecule works by increasing the normal levels of CEP290 protein in the photoreceptors of the eye and improving the function of the retina in daytime viewing conditions.

The treatment was designed for patients diagnosed with Leber’s congenital amaurosis (LCA), an eye disorder that mainly affects the retina, who have a CEP290 mutation, which is one of the genes most commonly implicated in patients with the disease. Patients with this form of ACL suffer from severe visual impairment, which usually begins in childhood.

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“Our results set a new standard for potential biological enhancements,” said co-lead author Artur Cideciyan, PhD, research professor of Ophthalmology at Penn Medicine’s Scheie Eye Institute. “Importantly, we established a comparator for gene-editing therapies currently underway for the same disease, which will allow us to compare the relative merits of two different interventions.”

In a 2019 study published in Nature Medicine, Cideciyan and colleagues, including Dr. Samuel G. Jacobson, found that repeated sepofarsen injections every three months resulted in continued vision gains in 10 patients.

The eleventh patient, whose treatment is detailed in the last article, received only one injection and was examined over a period of 15 months. Before treatment, the patient had reduced visual acuity, small visual fields, and no night vision. After the initial dose, the patient decided to forego quarterly maintenance doses, as regular dosing could lead to cataracts.

Big improvement in a ‘micro’ dose

After a single injection of sepofarsen, more than a dozen measurements of visual function and retinal structure showed great improvements supporting a biological effect of the treatment. A key finding of the case was that this biological effect was relatively slow absorption. The researchers saw an improvement in vision after one month, but the patient’s vision reached a maximum effect after the second month. Most surprisingly, the improvements were sustained when tested more than 15 months after the first and only injection.

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According to the researchers, the extended durability of vision improvement was unexpected and provides implications for the treatment of other ciliopathies, the name of the large category of diseases associated with genetic mutations that encode faulty proteins, resulting in abnormal function of the cilia, a protruding sensory organelle found in cells.

“This work represents a really exciting direction for RNA antisense therapy. It’s been 30 years since new drugs that use antisense RNA oligonucleotides came out, although everyone realized that these treatments were very promising, ”said Jacobson. “The unexpected stability of the ciliary transition zone observed in the patient leads to reconsideration of dosing schedules for sepofarsen, as well as other therapies targeting the cilium.”

One reason antisense oligonucleotide has been shown to be successful in treating this rare disease, according to the researchers, is that these tiny RNA molecules are small enough to enter the cell nucleus, but are not removed very quickly, for so they stay long enough to do their job.

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For future studies, the Penn authors are planning specific gene therapies for other currently incurable blinding inherited retinal disorders.

Source: Penn Medicine

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