Long-term treatment of a genetic form of blindness

U.S. scientists at the University of Pennsylvania were able to achieve a lasting improvement in vision with a single injection of RNA therapy, targeting Leber's congenital amaurosis disease.  They reported their results in the journal Nature Medecine [ref. 1] . 

Leber's congenital amaurosis disease primarily affects the retina - the part of the eye that captures light and colors, and converts them into a nerve signal that is sent to the brain. People suffering from this disease usually have severely impaired vision from infancy, or even blindness. It is rarely progressive, but sometimes a worsening of symptoms is observed over time. Some of them include:

• curtain of the eyes (cataracts)
• uncontrolled movement of the eye
• intolerance to bright light
• squint
• extreme farsightedness , etc.

Leber congenital amaurosis is a genetic disease. Mutations in a gene called CEP290 are among the most common causes of developing the disease - between 15 and 22%  of cases are due to defects in it [ref. 2] .

One of the most common mutations, 2991+1655A>G, was also the subject of the therapy in the clinical trial conducted at the Scheie Eye Institute in Pennsylvania.

Antisense-RNA oligonucleotides are molecules of RNA that target the messanger RNA (mRNA) of a gene, i.e. the intermediary molecule between the genetic information encoded in the gene and the final functional unit of the cell which is the protein. Binding of the antisense-RNA to the targeted mRNA can lead to a number of consequences, such as its change. 

This is also the purpose of therapy against Leber congenital amaurosis. The main idea of the researche is to inject a specially created antisense-RNA molecule to recognize the early defective mRNA, which would encode the defective CEP290 gene, and change it to eliminate the aforementioned 2991+1655A>G mutation. 

The team recruited 11 patients for the clinical trial suffering from the disease with a detected 2991+1655A>G mutation. The original protocol included an antisense-RNA injection called sepofarsen every 3 months. However, the last patient, patient 11, refused to continue treatment  after the first dose, as he felt a significant improvement in symptoms and wanted to reduce the risk of side effects after the administration of subsequent doses of the preparation.

The case of patient 11 is the subject of the article published in Nature Medecine. It is of interest because the patient received only one dose of the therapy, but the results of the follow-up showed that his vision improvement was comparable to that of the other treatment participants who received all the necessary doses. 

The patient was followed within 15 months after the first and only dose of sesopharsen was administered. The researchers reported significant improvements in the participant's vision and in the structure of his retina, with the peak of efficacy being the third month after therapy. There was a slight decrease in effectiveness by month 15, but nevertheless the symptoms were still significantly improved.

A possible explanation, according to the team of researchers, is the slow degradation of the antisenes-RNA entering the nucleus of the cell, as well as the relatively long life of the properly synthesized functional CEP290 protein.