Abstract

Photoreceptor ciliopathies constitute the most common molecular mechanism of the childhood blindness Leber congenital amaurosis. Ten patients with Leber congenital amaurosis carrying the c.2991+1655A>G allele in the ciliopathy gene centrosomal protein 290 (CEP290) were treated (ClinicalTrials.gov no. NCT03140969) with intravitreal injections of an antisense oligonucleotide to restore correct splicing. There were no serious adverse events, and vision improved at 3 months. The visual acuity of one exceptional responder improved from light perception to 20/400.

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All relevant patient-level data are displayed in the figures. All requests for data will be reviewed by ProQR Therapeutics and the universities involved to verify whether the request is subject to any intellectual property or confidentiality obligations. Patient-related data may be subject to confidentiality. Any data that can be shared will be released.

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Acknowledgements

This work was supported by clinical trial contracts from ProQR Therapeutics to site principal investigators A.V.C., B.P.L., and S.R.R.

Author information

Affiliations

  1. Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    • Artur V. Cideciyan
    • , Samuel G. Jacobson
    • , Jason Charng
    • , Alexandra V. Garafalo
    • , Alejandro J. Roman
    •  & Alexander Sumaroka
  2. Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA

    • Arlene V. Drack
    • , Ian C. Han
    • , Maria D. Hochstedler
    • , Wanda L. Pfeifer
    • , Elliott H. Sohn
    •  & Stephen R. Russell
  3. Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA, USA

    • Allen C. Ho
  4. ProQR Therapeutics, Leiden, the Netherlands

    • Magali Taiel
    • , Michael R. Schwartz
    • , Patricia Biasutto
    • , Wilma de Wit
    • , Peter Adamson
    • , David M. Rodman
    • , Gerard Platenburg
    •  & Maria D. Tome
  5. UCL Institute of Ophthalmology, London, UK

    • Michael E. Cheetham
    •  & Peter Adamson
  6. Department of Ophthalmology, Ghent University and Ghent University Hospital, Ghent, Belgium

    • Irina Balikova
    • , Fanny Nerinckx
    • , Julie De Zaeytijd
    • , Caroline Van Cauwenbergh
    •  & Bart P. Leroy

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Contributions

A.V.C. and S.G.J. contributed to the clinical study design and protocol development; performed clinical investigation of patients; reviewed, analyzed, and interpreted the data; and wrote the draft manuscript and its revisions. M.T., M.R.S., P.B., W.d.W., P.A., D.M.R., G.P., and M.D.T. developed the clinical study protocol, reviewed the data, and contributed to all drafts of the manuscript. A.V.D., B.P.L., and S.R.R. performed the clinical investigation of patients, contributed to the clinical study design and protocol development, and contributed to all drafts of the manuscript. A.C.H., F.N., and S.R.R. performed the injections. J.C., A.V.G., A.J.R., A.S., I.C.H., M.D.H., W.L.P., E.H.S., I.B., J.D.Z., and C.V.C. supported clinical investigation of the patients. A.J.R. performed the statistical analyses. P.B., P.A., and M.E.C. performed in vitro experiments determining clinical dosing strategy.

Competing interests

M.T., M.R.S., P.B., W.d.W., P.A., D.M.R., G.P., and M.D.T. are employees and stock holders of ProQR Therapeutics. M.E.C. was a consultant for ProQR Therapeutics.

Corresponding authors

Correspondence to Artur V. Cideciyan or Samuel G. Jacobson.

Extended data

  1. Extended Data Fig. 1 OCT scans along the horizontal meridian crossing the fovea at baseline and months 1 and 3 following the first injection.

    Ocular instability prevented imaging in some eyes; in other eyes only a single image per visit was available in the central clinical trial database. na, not available (P9 and P10 have not reached the M3 time point)

  2. Extended Data Fig. 2 En face imaging at baseline and months 1 and 3 following the first injection.

    Ocular instability prevented imaging in some or all visits of P1, P5, P6, and P8. Only a single image was available per visit in the central clinical trial database. P9 and P10 have not reached the M3 time point. +, infrared reflectance image obtained instead of infrared autofluorescence image

  3. Extended Data Fig 3 Visual acuity results at baseline and months 1 through 6 following injection(s).

    a, Visual acuity results recorded in both eyes of all ten subjects as of the interim analysis cut-off date. Treated eyes are larger up-triangles and untreated contralateral eyes are smaller down-triangles. Minor shifts are introduced to allow visibility of symbols that would otherwise overlap. b, Change in acuity from baseline. The first 3 months of the graph are duplicated in Fig. 1d of the main report. c, Interocular difference (treated eye minus untreated eye) between acuities. Larger symbols in panels b and c are averages from 10 patients at baseline and month 1, 8 patients at months 2 and 3, 6 patients at months 4 and 5, and 4 patients at month 6. Smaller symbols show the individual data points. Error bars, ±1 s.d. Linear mixed-effects models were used for the statistical analysis

  4. Extended Data Fig 4 Oculomotor instability results at baseline, month 3, and month 6 following injection(s).

    a,b, Oculomotor instability as log10 of the variation of the radial distance (in mm) of the center of pupil from the mean normal primary gaze locus recorded over a 30-s epoch in a darkened room with (a) or without (b) a bright blue fixation light. Treated eyes are larger up-triangles and untreated contralateral eyes are smaller down-triangles. Minor shifts are introduced to allow visibility of symbols that would otherwise overlap. c,d, Change in instability from baseline. e,f, Interocular difference (treated eye minus untreated eye) between ocular instabilities recorded. Larger symbols in panels b and c are averages from 10 patients at baseline, 7 patients at month 3, and 4 patients at month 6. Smaller symbols show the individual data points. Error bars, ±1 s.d. Linear mixed-effects models were used for the statistical analysis

  5. Extended Data Fig 5 FST threshold results at baseline and months 1 through 6 following injection(s).

    a,b, FST results recorded in both eyes of all subjects. All data are plotted on the left ordinate scale except for the connected symbols of P7 which are plotted on the integrated luminance scale of the right ordinate. Symbols are averages of repeated FST thresholds obtained within each visit. Nominally, n = 10 repetitions were obtained but there was also some variation (mean = 9.4, mode = 10 samples). c,d, Change in threshold from baseline. The first 3 months of the graphs are duplicated in Fig. 1e,f of the main report. e,f, Interocular difference (treated eye minus untreated eye) between thresholds. Larger symbols in panels cf are averages from 10 patients at baseline; 9, 8, 10, and 8 patients at month 1; 7, 7, 7, and 7 patients at month 2; 7, 8, 8, and 8 patients at month 3; and 3, 4, 4, and 4 patients at month 6 for untreated red, treated red, untreated blue, and treated blue FSTs, respectively. Smaller symbols show the individual data points. Error bars, ±1 s.d. Linear mixed-effects models were used for the statistical analysis

  6. Extended Data Fig 6 Foveal subcellular anatomy in four of the eight patients who had analyzable recordings at baseline and 3 months in both eyes.

    a,b, Longitudinal reflectivity profiles overlaid on foveal OCT scans showing signals associated with intraretinal anatomical features at baseline and month 3 in both eyes. c,d, Changes to outer retinal peaks in terms of backscatter intensity and the peaks used to measure inner (IS) and outer segment (OS) lengths proximal and distal to the connecting cilium, respectively. e,f, Bar graphs of the IS and OS length obtained from a single recording. na, not available due to foveal atrophy

  7. Extended Data Fig 7 Best mobility levels passed at baseline and months 1 through 6 following injection(s).

    a, Mobility results recorded in both eyes of all subjects. b, Change in mobility from baseline. c, Interocular difference (treated eye minus untreated eye) between mobility levels. Larger symbols in panels bc are averages from 9 patients at baseline, 8 patients at month 1, 7 patients at months 2 and 3, and 4 patients at month 6. Error bars, ±1 s.d.

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DOI

https://doi.org/10.1038/s41591-018-0295-0