Leber congenital amaurosis due to CEP290 ciliopathy is being explored by treatment with the antisense oligonucleotide (AON) sepofarsen. One patient who was part of a larger cohort (ClinicalTrials.gov NCT03140969) was studied for 15 months after a single intravitreal sepofarsen injection. Concordant measures of visual function and retinal structure reached a substantial efficacy peak near 3 months after injection. At 15 months, there was sustained efficacy, even though there was evidence of reduction from peak response. Efficacy kinetics can be explained by the balance of AON-driven new CEP290 protein synthesis and a slow natural rate of CEP290 protein degradation in human foveal cone photoreceptors.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
All relevant patient-level data are displayed in the figures. All requests for data will be reviewed by ProQR Therapeutics and the University of Pennsylvania to verify whether the request is subject to any intellectual property or confidentiality obligations. Patient-related data might be subject to confidentiality. Any data that can be shared will be released.
Hanany, M., Rivolta, C. & Sharon, D. Worldwide carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases. Proc. Natl Acad. Sci. USA 117, 2710–2716 (2020).
den Hollander, A. I. et al. Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. Am. J. Hum. Genet. 79, 556–561 (2006).
Cideciyan, A. V. et al. Centrosomal-ciliary gene CEP290/NPHP6 mutations result in blindness with unexpected sparing of photoreceptors and visual brain: implications for therapy of Leber congenital amaurosis. Hum. Mutat. 28, 1074–1083 (2007).
Cideciyan, A. V. et al. Cone photoreceptors are the main targets for gene therapy of NPHP5 (IQCB1) or NPHP6 (CEP290) blindness: generation of an all-cone Nphp6 hypomorph mouse that mimics the human retinal ciliopathy. Hum. Mol. Genet. 20, 1411–1423 (2011).
Jacobson, S. G. et al. Outcome measures for clinical trials of Leber congenital amaurosis caused by the intronic mutation in the CEP290 gene. Invest. Ophthalmol. Vis. Sci. 58, 2609–2622 (2017).
Cideciyan, A. V. & Jacobson, S. G. Leber congenital amaurosis (LCA): potential for improvement of vision. Invest. Ophthalmol. Vis. Sci. 60, 1680–1695 (2019).
Cideciyan, A. V. et al. Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect. Nat. Med. 25, 225–228 (2019).
Sumaroka, A. et al. Treatment potential for macular cone vision in Leber congenital amaurosis due to CEP290 or NPHP5 mutations: predictions from artificial intelligence. Invest. Ophthalmol. Vis. Sci. 60, 2551–2562 (2019).
Krishnan, A. K. et al. Transient pupillary light reflex in CEP290- or NPHP5-associated Leber congenital amaurosis: latency as a potential outcome measure of cone function. Vis. Res. 168, 53–63 (2020).
Dulla, K. et al. Splice-modulating oligonucleotide QR-110 restores CEP290 mRNA and function in human c.2991+1655A>G LCA10 models. Mol. Ther. Nucleic Acids 12, 730–740 (2018).
Walia, S. et al. Visual acuity in patients with Leber’s congenital amaurosis and early childhood-onset retinitis pigmentosa. Ophthalmology 117, 1190–1198 (2010).
Trapani, I. & Auricchio, A. Seeing the light after 25 years of retinal gene therapy. Trends Mol. Med. 24, 669–681 (2018).
Maeder, M. L. et al. Development of a gene-editing approach to restore vision loss in Leber congenital amaurosis type 10. Nat. Med. 25, 229–233 (2019).
Doudna, J. A. The promise and challenge of therapeutic genome editing. Nature 578, 229–236 (2020).
Schoch, K. M. & Miller, T. M. Antisense oligonucleotides: translation from mouse models to human neurodegenerative diseases. Neuron 94, 1056–1070 (2017).
Henry, S. P. et al. Antiviral activity and ocular kinetics of antisense oligonucleotides designed to inhibit CMV replication. Invest. Ophthalmol. Vis. Sci. 42, 2646–2651 (2001).
Kocaoglu, O. P. et al. Photoreceptor disc shedding in the living human eye. Biomed. Opt. Express 7, 4554–4568 (2016).
Baehr, W. et al. Insights into photoreceptor ciliogenesis revealed by animal models. Prog. Retin Eye Res. 71, 26–56 (2019).
Potter V. L., Moye A. R., Robichaux M. A., Wensel T. G. Superresolution microscopy reveals photoreceptor-specific subciliary location and function of Cep290. Preprint at bioRxiv https://doi.org/10.1101/2020.10.28.357806 (2020).
Littink, K. W. et al. A novel nonsense mutation in CEP290 induces exon skipping and leads to a relatively mild retinal phenotype. Invest. Ophthalmol. Vis. Sci. 51, 3646–3652 (2010).
Pasadhika, S. et al. Differential macular morphology in patients with RPE65-, CEP290-, GUCY2D-, and AIPL1-related Leber congenital amaurosis. Invest. Ophthalmol. Vis. Sci. 51, 2608–2614 (2010).
Yzer, S. et al. Ocular and extra-ocular features of patients with Leber congenital amaurosis and mutations in CEP290. Mol. Vis. 18, 412–425 (2012).
Collison, F. T., Park, J. C., Fishman, G. A., McAnany, J. J. & Stone, E. M. Full-field pupillary light responses, luminance thresholds, and light discomfort thresholds in CEP290 Leber congenital amaurosis patients. Invest. Ophthalmol. Vis. Sci. 56, 7130–7136 (2015).
Sheck, L. et al. Leber congenital amaurosis associated with mutations in CEP290, clinical phenotype, and natural history in preparation for trials of novel therapies. Ophthalmology 125, 894–903 (2018).
Feldhaus, B. et al. CEP290 mutation spectrum and delineation of the associated phenotype in a large German cohort: a monocentric study. Am. J. Ophthalmol. 211, 142–150 (2020).
Ferris, F. L. 3rd, Kassoff, A., Bresnick, G. H. & Bailey, I. New visual acuity charts for clinical research. Am. J. Ophthalmol. 94, 91–96 (1982).
Sunness, J. S. et al. Low luminance visual dysfunction as a predictor of subsequent visual acuity loss from geographic atrophy in age-related macular degeneration. Ophthalmology 115, 1480–1488 (2008).
Roman, A. J. et al. Quantifying rod photoreceptor-mediated vision in retinal degenerations: dark-adapted thresholds as outcome measures. Exp. Eye Res. 80, 259–272 (2005).
Roman, A. J., Cideciyan, A. V., Aleman, T. S. & Jacobson, S. G. Full-field stimulus testing (FST) to quantify visual perception in severely blind candidates for treatment trials. Physiol. Meas. 28, N51–N56 (2007).
Jacobson, S. G. et al. Determining consequences of retinal membrane guanylyl cyclase (RetGC1) deficiency in human Leber congenital amaurosis en route to therapy: residual cone–photoreceptor vision correlates with biochemical properties of the mutants. Hum. Mol. Genet. 22, 168–183 (2013).
Klein, M. & Birch, D. G. Psychophysical assessment of low visual function in patients with retinal degenerative diseases (RDDs) with the Diagnosys full-field stimulus threshold (D-FST). Doc. Ophthalmol. 119, 217–224 (2009).
Collison, F. T., Fishman, G. A., McAnany, J. J., Zernant, J. & Allikmets, R. Psychophysical measurement of rod and cone thresholds in Stargardt disease with full-field stimuli. Retina 34, 1888–1895 (2014).
Cideciyan, A. V. et al. Human cone visual pigment deletions spare sufficient photoreceptors to warrant gene therapy. Hum. Gene Ther. 24, 993–1006 (2013).
Cideciyan, A. V. et al. Reduced-illuminance autofluorescence imaging in ABCA4-associated retinal degenerations. J. Opt. Soc. Am. A 24, 1457–1467 (2007).
Herrera, W. et al. Retinal disease in Usher syndrome III caused by mutations in the clarin-1 gene. Invest. Ophthalmol. Vis. Sci. 49, 2651–2660 (2008).
Gibbs, D., Cideciyan, A. V., Jacobson, S. G. & Williams, D. S. Retinal pigment epithelium defects in humans and mice with mutations in MYO7A: imaging melanosome-specific autofluorescence. Invest. Ophthalmol. Vis. Sci. 50, 4386–4393 (2009).
Saletu, B. & Grünberger, J. Drug profiling by computed electroencephalography and brain maps, with special consideration of sertraline and its psychometric effects. J. Clin. Psychiatry 49, 59–71 (1988).
Granholm, E. et al. Tropicamide effects on pupil size and pupillary light reflexes in Alzheimer’s and Parkinson’s disease. Int. J. Psychophysiol. 47, 95–115 (2003).
Cideciyan, A. V. et al. Pseudo-fovea formation after gene therapy for RPE65-LCA. Invest. Ophthalmol. Vis. Sci. 56, 526–537 (2014).
Cideciyan, A. V. et al. Macular function in macular degenerations: repeatability of microperimetry as a potential outcome measure for ABCA4-associated retinopathy trials. Invest. Ophthalmol. Vis. Sci. 53, 841–852 (2012).
This work was supported by a clinical trial contract from ProQR Therapeutics to A.V.C., administered by the University of Pennsylvania. There was also partial support by the National Institutes of Health grant UL1 TR001878.
M.R.S. and A.G. are employees of ProQR Therapeutics. All other authors have no competing financial interests.
Peer review information Nature Medicine thanks Hendrik Scholl and the other, anonymous, reviewers for their contribution to the peer review of this work. Joao Monteiro was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended Data Fig. 1 Retinal Structure, Visual Acuity and Light Sensitivity of the Study Patient P11 at Baseline and Three Months After Treatment.
a, P11 retained a macular island of RPE and photoreceptor cells in both eyes before treatment as demonstrated by near-infrared (melanin) autofluorescence (left) and cross-sectional OCT imaging (right). T, temporal retina, N, nasal retina. b-d, Visual acuity and light sensitivity (red and blue FSTs) for both eyes of P11 compared to five others (P1-P5) at baseline. e-g, Visual acuity and sensitivity changes from baseline at 3 months after intravitreal injection of 160 µg sepofarsen into one eye. Treated eyes are larger up triangles, untreated eyes are smaller down triangles. h-j, Interocular difference of visual acuity and sensitivity at 3 months. b-j, Black symbols are data from P11, whereas gray symbols are from P1-P5 who received the same initial dose. After 3 months, P11 was continued to be followed without intervention whereas P1-P5 were redosed. Symbols in panels c and d are the mean value of 6-20 replicates. Symbols in panels b, e, and h are individual data points. Symbols in f, g, i and j are differences of means from 6-20 replicates.
a, Change in best corrected ETDRS acuity from baseline where both eyes were symmetric. After treatment, there was a larger improvement in the treated eye compared to untreated eye. Acuity in the treated eye remained asymmetric and better than baseline at 15 months. b, c, Specialized assessments of low-luminance visual acuity (LLVA) starting at 3 months after treatment using neutral density filters, +1ND (b) and +2ND (c). Symbols in panels a,b, and c are individual data points. d, Interocular difference of different acuity measures. Thick gray lines represents the 3-parameter log Normal fit to data. Symbols in panel d are differences between individual data points from each eye. Panel d is duplicated in Fig. 1a.
a-d, Change in dark adapted (DA, a, c) and light adapted (LA, b, d) FST thresholds from baseline for red and blue stimuli. There is substantial improvement in the treated eye (larger triangles) by all four measures. DA sensitivities peak at 2-3 months and show slow decline after ~7 months. LA sensitivities peak later between 5-9 months and show a slow decline thereafter. All four measures remain above baseline at 15 months. Gray dashed line represents no change from baseline. Symbols and error bars represent mean±1SD from 6-20 technical replicates at each time point for each test. e, f, Interocular difference of DA (e) and LA (f) FST thresholds for red (red symbols) and blue (blue symbols) stimuli. Kinetics show peak improvement followed by slow decline. Symbols in panels e and f are differences of means from 6-20 replicates. Thick gray line represents the 3-parameter log Normal fit to data. Panel e is duplicated in Fig. 1b.
Extended Data Fig. 4 Changes to functional vision evaluated with visual navigation challenge (VNC) obstacle course.
a, b, Best mobility levels passed in the treated eye (up triangle) and in the untreated eye (down triangle). There is a rapid improvement with treatment peaking at month 1 and sustained through month 15. The raw score representing number of course levels that was navigable (a) and change of navigable levels from baseline performance (b) are shown for both treated and untreated eyes. Symbols are individual data points. c, The interocular difference of the number of course levels that was navigable. Treated eye that was initially the worse eye becomes the better eye. Symbols are the differences between individual data points from each eye.
Extended Data Fig. 5 Changes in objective measures of visual function with dark adapted pupillometry.
a, Raw traces of pupillary diameter as a function of time for brief (1s) red flashes of 50 (thinner traces) and 500 (thicker traces) phot-cd.m−2 luminance at different visits. Vertical gray dashed lines represent the onset of the flash. Stimulus marker and scale bar are shown. b, Magnified view showing the early phases of constriction in the untreated and treated eyes at baseline (black) and month 3 (red) for the two stimuli. Horizontal dashed lines mark the criteria of 0.3 mm constriction used to define latency. Arrows demonstrate the acceleration of the response. c,d, Interocular differences of latency as a function of time after treatment for both red stimuli. Results show pupil constrictions accelerating to a peak at month 3 in the treated eye. Symbols are the differences of means from 1-3 replicates. Panels are duplicated in Fig. 1c.
a, Near-infrared excited autofluorescence (NIRAF) images of the macular region in the untreated and treated eyes showing an elliptical region of preserved RPE melanization in both eyes qualitatively unchanged through month 15. b, c Normalized NIRAF intensity profiles as a function of retinal eccentricity in both horizontal (b) and vertical meridian (c). Month 12 (red traces) and baseline visit (black traces) are highlighted to demonstrate lack of change. Vertical dashed black line represents the fovea. d, Foveal NIRAF intensity used for normalization of the traces in panels b and c. Symbols are individual data points.
OCT scans along the horizontal meridian crossing the fovea illustrating the laminar architecture observed through month 15 in the treated and untreated eyes. Nasal (N), temporal retina (T) are marked and scale bars are provided.
Extended Data Fig. 8 Quantification of the photoreceptor sublaminae for 15 months following treatment.
a, Representative OCT scan showing the foveal longitudinal reflectivity profile (LRP) and the three thickness parameters (ONL thickness, IS length, and OS length) and one intensity parameter (IS/OS intensity) quantified. b-e, Photoreceptor sublaminae parameters consisting of outer nuclear layer (ONL) thickness (b), inner segment (IS) length (c), outer segment (OS) length (d), and IS/OS intensity (e) are shown. Seven panels on each row represent data from 7 retinal locations as a function of time after treatment. Gray and black lines delimit test-retest variability in the untreated and treated eye, respectively. Black arrows point to transient changes in IS length and IS/OS intensity between months 2 and 5 in the treated eye (black up triangle). T, temporal retina; N, nasal retina. Each symbol in panels b-e represents the average of three replicates. Interocular differences of the IS/OS intensity at fovea and 1° T and N eccentricities shown in panel e are plotted in Fig. 1d.
a, Eye movement data during fixation to a large visible red target are shown in spatial (left) and spatiotemporal (right) coordinates. Spatial distribution of fixation clouds is shown on standard circles (radii at 1.65°, 5°, and 10°) representing the macular region centered on the anatomical foveal depression. Spatiotemporal distribution of eye movements is shown on chart records for x and y directions; up is nasal retina for x and superior retina for y. b, Fixation instability as a function of time after treatment is unchanged in both the treated (up-triangle) and untreated eye (down-triangle). Symbols are individual data points.
About this article
Cite this article
Cideciyan, A.V., Jacobson, S.G., Ho, A.C. et al. Durable vision improvement after a single treatment with antisense oligonucleotide sepofarsen: a case report. Nat Med (2021). https://doi.org/10.1038/s41591-021-01297-7