A scientific study published only a few days ago has attracted the attention of the ophthalmological world. The research group led by Cideciyan has investigated the effectiveness of antisense oligonucleotide therapy in a subtype of Leber's congenital amaurosis with a mutation in the CEP290 gene.
CEP290 stands for centrosomal protein 290. Leber's congenital amaurosis is a top etiological cause of blindness at a young age. It refers to a group of retinal diseases that can present congenitally or within the first year of life with marked visual loss or even blindness. Oculodigital phenomenon can often be observed in affected children. This is noticeable as follows: The children press on their eyes with their fingers to trigger a light appearance.1 With increasing age, it is also possible to perform perimetry. Perimetric examinations reveal residual central visual fields. There may also be reduced night vision and colour vision deficits. Leber's congenital amaurosis is usually inherited in an autosomal recessive manner. A mutation of the following genes may be present: AIPL1, CEP290, CRB1, CRX, GUCY2D, IMPDH1, IQCB1, KCNJ13, LCA5, NMNAT1, RD3, RDH12, RPGRIP1, SPATA7, RPE65 and TULP1.1
Experimental therapy with a single injection of the RNA therapeutic agent called sepofarsen was associated with a one-year improvement in visual acuity in one patient. Researchers at the University of Pennsylvania's Scheie Eye Institute recently published the groundbreaking data on this. The therapy led to significant changes in the fovea and thus to an improvement in visual acuity. The clinical trial was conducted at Penn Medicine. Study participants received intraocular injection therapy with the antisense oligonucleotide sepofarsen.1
The CEP290 gene is fundamentally involved in cilia development. A mutation or defect of the CEP290 gene can lead to a variety of different diseases, which are grouped under the umbrella term ciliopathies. If different organs are affected, this can be associated with phenotypic variability and a wide spectrum of syndromes. A mutation of the CEP290 gene can lead to isolated ciliopathies, as well as to ciliopathy-associated syndromes. Leber's congenital amaurosis and retinitis pigmentosa are among such isolated ciliopathies. In ciliopathy-associated syndromes, other organs such as the kidney, heart, liver, pancreas, lung, central nervous system and ear may be affected in addition to the eyes.2-7
The RNA therapeutic agent sepofarsen works by intraocularly increasing CEP290 protein towards normal levels within the photoreceptors. This is associated with an improvement in retinal function in daylight. In a previous study from 2019, visual acuity improvement was achieved in 10 patients with sepofarsen injections at 3-month intervals.8 The current publication from this year is about a very special case (ClinicalTrials.gov NCT03140969). In one patient, only one sepofarsen injection was sufficient to achieve improved vision. The follow-up time was 15 months. At baseline, the patient had markedly reduced visual acuity, significant perimetric defects and also suffered from night blindness. Visual acuity improvement was evident as early as 1 month after the sepofarsen injection and peaked at month 3. This improved visual acuity was maintained 15 months after injection.1
One reason for this continued success of the antisense oligonucleotide sepofarsen may be its small size. The RNA molecule is able to enter the interior of the cell nucleus. At the same time, it remains there for a longer period of time and can thus ensure a normally high CEP290 protein level. In addition, CEP290 protein degradation progresses only slowly in the cones of the human eye. The combination of these two conditions may explain the long-lasting therapeutic effect in the present patient.1
References:
1. Cideciyan A.V. et al (2021). Durable vision improvement after a single treatment with antisense oligonucleotide sepofarsen: a case report. Nat Med (2021).
2. Lopes C.A.M. et al. (2011). Centriolar satellites are assembly points for proteins implicated in human ciliopathies, including oral - facial - digital syndrome 1. Journal of Cell Science 2011; Vol. 124, 600 - 612.
3. Mockel A. et al. (2011). Retinal dystrophy in Bardet - Biedl syndrome and related syndromic ciliopathies. Retinal and Eye 2011; Vol. 30, 258 - 274.
4. Hurd T.W. et al. (2011). Mechanisms of nephronophthisis and related ciliopathies. Nephron Experimental Nephrology 2011; Vol. 118, 9 - 14.
5. Harris P.C. et al. (2009). Ziliopathien: Springer Medizin Verlag 2009, medgen 2009; Vol. 21, 14 - 20.
6. Hosch J. et al. (2011). RPGR: Role in the photoreceptor cilium, human retinal disease and gene therapy. Ophthalmic Genetics 2011; Vol. 32 (1), 1 - 11.
7. Badano J.L. et al. (2006). The Ciliopathies: An Emerging Class of Human Genetic Disorders. Ophthalmic Genetics 2006; Vol. 7, 125 - 148.
8. Cideciyan A.V. et al. (2019). Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect. Nat Med. 2019 Feb;25(2):225-228.