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Durable vision improvement after a single treatment with antisense oligonucleotide sepofarsen: a case report

Abstract

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.

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Fig. 1: Time course of vision improvement and durability over 15 months after a single treatment.
Fig. 2: Improvement of foveal sensitivity, expansion of visual field and predicted effect on reading performance.

Data availability

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.

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Acknowledgements

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.

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Affiliations

Authors

Contributions

A.V.C. and S.G.J. contributed to the clinical study design and protocol development, performed clinical investigation of patients, collected, reviewed, analyzed and interpreted the data and wrote the draft manuscript. A.C.H. performed the intravitreal injections. A.V.G., A.J.R., A.S., A.K.K. and M.S. collected and analyzed data. All authors contributed to the revision of the manuscript.

Corresponding author

Correspondence to Artur V. Cideciyan.

Ethics declarations

Competing interests

M.R.S. and A.G. are employees of ProQR Therapeutics. All other authors have no competing financial interests.

Additional information

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

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.

Extended Data Fig. 2 Evaluation of visual acuity.

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.

Extended Data Fig. 3 Evaluation of light sensitivity with FST.

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.

Extended Data Fig. 6 Lack of discernable changes in RPE melanization.

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.

Extended Data Fig. 7 Retinal cross-sectional structure.

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.

Extended Data Fig. 9 Fixational stability.

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.

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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

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