Single injection reverses blindness in patient with rare genetic disease

A Penn Medicine patient with a genetic form of childhood blindness acquired vision, which lasted for over a year, after receiving a single injection of experimental RNA therapy into the eye. The clinical trial was conducted by researchers at the Scheie Eye Institute at the Perelman School of Medicine at the University of Pennsylvania. Results of the case, detailed in an article published today in Nature medicine, show that the treatment led to marked changes in the fovea, the most important locus of human central vision.

Treatment was designed for patients diagnosed with Leber’s congenital amaurosis (LCA) – an eye disorder that primarily affects the retina – who have a CEP290 mutation, which is one of the genes most commonly involved in patients with disease. Patients with this form of stroke suffer from severe visual disturbances, which usually begin in childhood.

“Our results set a new standard for the biological improvements possible with antisense oligonucleotide therapy in stroke caused by CEP290 mutations,” said co-lead author Artur V. Cideciyan, Ph.D., research professor of ophthalmology. “Importantly, we have established a comparator for gene editing therapies currently underway for the same disease, which will allow the relative merits of two different interventions to be compared.”

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

In a 2019 study published in Nature medicine, Cideciyan, Jacobson, and colleagues found that repeated injections of sepofarsene every three months resulted in continuous vision gains in 10 patients. The eleventh patient, whose treatment was detailed in the last Nature medicine 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 forgo quarterly maintenance doses, as regular dosing could lead to cataracts.

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. One of the main conclusions of this case was that this biological effect was relatively slow to be absorbed. The researchers found improvement in vision after one month, but the patient’s vision peaked after the second month. More strikingly, the improvements remained when tested for more than 15 months after the first and only injection.

According to the researchers, the prolonged durability of the improvement in vision was unexpected and has implications for the treatment of other ciliopathies – the name of the broad category of diseases associated with genetic mutations encoding defective proteins, resulting in the abnormal function of the eyelashes, a protruding sensory organelle. found on cells.

“This work represents a truly exciting direction for antisense RNA therapy. It has been 30 years since there have been any new drugs using antisense RNA oligonucleotides, although everyone has realized that these treatments hold great promise, ”said Jacobson. “The unexpected stability of the ciliary transition zone noted in the patient prompts reconsideration of sepofarsen dosing regimens, as well as other therapies targeted to the eyelash.”

According to the researchers, one of the reasons the antisense oligonucleotide has been shown to be effective in treating this rare disease is that these tiny RNA molecules are small enough to enter the cell nucleus, but are not eliminated. very quickly, so they stay long enough to do their job.

“There is now, at least in the eye area, a series of clinical trials using antisense oligonucleotides for different genetic defects brought about by the success of the ACV work associated with CEP290 by Drs Cideciyan and Jacobson,” said Joan O’Brien, MD, chair of ophthalmology at the Perelman School of Medicine and director of the Scheie Eye Institute

For future studies, Penn’s authors are planning gene-specific therapies for other blinding hereditary retinal disorders that are currently incurable.