Mutation-specific RNA therapy reverses childhood blindness

RNA therapy restores vision

Date: 6th April 2021

Inherited retinal diseases (IRDs) are a group of over 300 monogenic causes of visual disability, and currently only one form is treatable.  Leber congenital amaurosis (LCA) is one of the most severe forms of IRD, it is a childhood-onset blindness and is caused my mutations in ciliary transition zone proteins, mostly commonly in CEP290 (Centrosomal protein 290). Currently, a LCA treatment is being explored for CEP290 ciliopathy in a clinical trial using an antisense RNA oligonucleotide (AON) called sepofarsen.  Now, researchers report durable vision improvement after a single treatment with sepofarsen for up to 15 months.

The clinical trial, NCT03140969, was designed to evaluate the safety and tolerability of QR-110 (sepofarsen) administered via intravitreal injection in subjects with LCA due to the CEP290 p.Cys998X mutation. The therapy was a 17-mer 2′-O-methyl-modified phosphorothioate RNA AON, and was to be administered every 3 months.  The RNA therapy was designed to restore correct splicing in the retina, increasing the normal CEP290 levels of protein in the photoreceptors, improving retinal function.  Results from the first 10 participants showed efficacy however, the last patient to be enrolled received one dose and then declined repeat dosing to avoid potential lenticular adverse events (cataracts).

Now, researchers at the Perelman School of Medicine, University of Pennsylvania, US, and in part funded by ProQR Therapeutics, a biotechnology company based in the Netherlands, developing RNA therapies for rare genetic diseases, have reported the unexpected extended durability of vision improvement by a single dose of sepofarsen, providing new implications of dosing for this and other cilopathies and providing new standards of biological improvements that can be achieved with AONs.

The participant demonstrated substantial improvements in all recorded subjective and objective measurements of visual functions as well as retinal structure.  The efficacy of the treatment was detectable at 1 month, then had peaked by 3 months, but unexpectedly remained better than the pre-treatment baseline for up to 15 months.  Whilst, the synthesis and degradation rates of transition zone proteins are mostly unknown, the team suggest that the slow natural rate of CEP290 protein degradation in the photoreceptors may account for the extended improvement of vision.

Conclusions and future applications

The team here have demonstrated an unexpected stability of vision restoration by RNA therapy for LCA. RNA therapy using naked AONs have been thought of as a more repetitive but less invasive treatment than adeno-associated virus-vectored (AAV) in vivo genomic editing which is also been trialled for LCA.  Now, this work here warrants reconsideration of dosing regimes for RNA therapy for LCA and other cilium-targeted therapies.

In the future, the Penn researchers are planning to extend the study, looking to develop gene-specific therapies for other currently incurable inherited retinal disorders.

This work adds to the ongoing efforts to develop gene therapies to restore vision, and is not the only study to reveal unexpected results from such nascent studies.  Recent AAV gene therapy to treat Leber hereditary optic neuropathy (LHON) showed that in 78% of cases unilateral injections significantly but suprisingly improved vision in both eyes.  LCA was also the target of the world’s first ever in vivo gene editing in humans which was carried out by Allergen and Editas to treat Leber congenital amaurosis 10 (LCA10) just over a year ago.

Other works have addressed loss of sight due to ageing or injury, such as restoring youthful DNA methylation patterns to promote axon regeneration, or gene therapy to deliver an adapter molecule, Protrudin, stimulating axon regeneration of damaged nerve fibres. The delivery of a highly photosensitive multi-characteristic opsin (MCO1) protein into retina bipolar cells has also been used to improve vision due to age related macular degeneration

The diversity of gene therapies becoming available for sight restoration is impressive and rapidly growing.  With many steps involved in the visual transduction cascade, the ability to target and restore or bypass each step will be a valuable tool for treating a wide-range of eye diseases.  A better understanding of the biological effects of such treatment will be invaluable to optimise which types of therapies are best suited for which disease and which patients, they will also inform the safest, most effective dosing regimes and treatment windows in which they should be applied.


For more information please see the press release from Penn Medicine


Cideciyan, A. V., S. G. Jacobson, A. C. Ho, A. V. Garafalo, A. J. Roman, A. Sumaroka, A. K. Krishnan, M. Swider, M. R. Schwartz and A. Girach (2021). “Durable vision improvement after a single treatment with antisense oligonucleotide sepofarsen: a case report.” Nature Medicine.