Single Dose of Antisense RNA Treatment Reverses Rare Form of Blindness

Inherited Retinal Disorders (IRDs) are a spectrum of ocular diseases caused by pathogenic mutations in over 250 genes such as RPE65, CEP290, etc. Leber Congenital Amaurosis (LCA) is a sub-type of IRD wherein patients suffer retinal malfunction and visual impairment. In a breakthrough clinical study of antisense RNA therapy, researchers at the University of Pennsylvania School of Medicine were able to reverse blindness with a single injection of CEP290-activating antisense RNA.

The authors have been working on finding a cure for the severe form of LCA, with childhood onset caused by CEP290 mutation, which disrupts the photoreceptors in the retina. In 2019, lead authors Dr. Cideciyan and Dr. Jacobson reported a new antisense oligonucleotide, sepofarsen which removed the mutated protein and replaced it with functional CEP290 protein; and hence improved retinal function in 10 LCA patients upon multiple injections.

Improvement in Visual Function

In this new study, they monitored the RNA therapy in the eleventh trial participant who received a single injection and was tested for improvement in vision and retinal structure for over 15 months. With an initial diagnosis of limited visual acuity and night blindness, the patient experienced remarkable improvements in visual function upon sepofarsen treatment.

The response was slow but long-lasting since the therapy resulted in improvement in several parameters after one month of the injection, with performance peaking after the second month. The therapy increased the visual field, restored CEP290 levels in the photoreceptor and retinal structure. Interestingly, the effect of therapy continued over 15 months, albeit with a single dose. One of the reasons for the success of prolonged activity of sepofarsen is its efficient uptake coupled with slow turnover in the photoreceptors. With this successful therapy for LCA, the team plans to design more gene-specific treatments for other inherited retinal disorders.

According to Dr. Cideciyan, these “results set a new standard of what biological improvements are possible with antisense oligonucleotide therapy in LCA caused by CEP290 mutations.” With other gene-editing therapies available for LCA, such as gene augmentation and CRISPR-based base editing, we can compare different gene therapy strategies to develop safer and efficient treatment options to cure congenital blindness.

Related Article: New and Improved Base-Editing Tool Helps Cure Blindness in Mice

Author

Sahana Shankar

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