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Partial recovery of visual function in a blind patient after optogenetic therapy

Nature Medicine volume 27, pages 1223–1229 (2021)Cite this article

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Abstract

Optogenetics may enable mutation-independent, circuit-specific restoration of neuronal function in neurological diseases. Retinitis pigmentosa is a neurodegenerative eye disease where loss of photoreceptors can lead to complete blindness. In a blind patient, we combined intraocular injection of an adeno-associated viral vector encoding ChrimsonR with light stimulation via engineered goggles. The goggles detect local changes in light intensity and project corresponding light pulses onto the retina in real time to activate optogenetically transduced retinal ganglion cells. The patient perceived, located, counted and touched different objects using the vector-treated eye alone while wearing the goggles. During visual perception, multichannel electroencephalographic recordings revealed object-related activity above the visual cortex. The patient could not visually detect any objects before injection with or without the goggles or after injection without the goggles. This is the first reported case of partial functional recovery in a neurodegenerative disease after optogenetic therapy.

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Fig. 1: Visual task coupled with EEG recordings.
Fig. 2: Decoding EEG data based on power spectrum amplitude modulation of occipital alpha oscillations.

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Data availability

All requests for the raw and analyzed data are promptly reviewed by GenSight Biologics to verify if they are subject to any intellectual property or confidentiality obligations. Patient-related data not included in the paper were generated as part of clinical trials and may be subject to patient confidentiality. Any data that can be shared will be released via a material transfer agreement. All raw and analyzed image data can be found at https://passageinnovation-my.sharepoint.com/:f:/g/personal/mtaiel_gensight-biologics_com/EkUITiEa4AxNs_YryLq7fT8BGpdYkXZMWWtDK6Wg-fcQfA.

Code availability

The code for the EEG data processing and spectral analysis is available at https://github.com/JBDSA/OptoRehabEEG.

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Acknowledgements

The PIONEER study group members were H. Akolkar, F. Arcizet, E. Bamberg, S. Bentobji, S. Bertin, E. Bochin, E. Boyden, A. Chaffiol, G. Chenegros, C. Ciavrs-Roux, C. Coen, D. Dagostinoz, M.-C. Despiau, M. Desrosiers, C. Devisme, G. Gauvain, J.-F. Girmens, A. Grimaud, R. Hosseini, C. Jaillard, L. Karbunarevic, J. Labbe, M. Laurent, J. P. Marques, O. Marre, G. Martin, R. Mecheri, N. Messeca, M. Michaelides, S. Mohand-Said, P. Pouget, P. Queromes, M. Roux, S. Sancho, I. Scarabin, P. Shabestary, W. Smith, A. Tufail, A. Webster. We thank M. Cattaneo for help with statistical analysis. We thank R. Benosman and his lab for their contribution to the development of the stimulation goggles and to the preclinical development. The study was supported by the following sources of funding: GenSight Biologics; French Programme Investissements d’Avenir IHU FOReSIGHT, no. ANR-18-IAHU-01 (J.-A.S., A.A. and I.A.) and RHU LIGHT4DEAF no. ANR-15-RHU-0001 (J.-A.S. and I.A.), BPI France (grant no. 2014-PRSP-15 to J.-A.S.), Foundation Fighting Blindness (J.-A.S. and I.A.) and Fédération des Aveugles de France and French National Research Agency (no. ANR-18-CHIN-0002 to A.A.).

Author information

Authors and Affiliations

  1. Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Institut de la Vision, Paris, France

    José-Alain Sahel, Angelo Arleo, Alexandre Delaux, Jean-Baptiste de Saint Aubert, Isabelle Audo, Jens Duebel, Serge Picaud & Deniz Dalkara

  2. Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    José-Alain Sahel & Joseph N. Martel

  3. Institut National de la Santé et de la Recherche Médicale-Centre d’Investigation Clinique 1423, Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, Paris, France

    José-Alain Sahel, Elise Boulanger-Scemama & Isabelle Audo

  4. Département d’Ophtalmologie, Fondation Ophtalmologique Rothschild, Paris, France

    José-Alain Sahel & Elise Boulanger-Scemama

  5. Streetlab, Institut de la Vision, Paris, France

    Chloé Pagot, Caroline de Montleau & Emmanuel Gutman

  6. GenSight Biologics, Paris, France

    Francesco Galluppi, Laure Blouin & Magali Taiel

  7. National Institute for Health Research Moorfields Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, UK

    Simona Degli Esposti

  8. Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland

    Botond Roska

  9. Department of Ophthalmology, University of Basel, Basel, Switzerland

    Botond Roska

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  1. José-Alain Sahel
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Contributions

J.-A.S. designed the study and wrote the paper. E.B.-S. collected the data. C.P. designed the functional vision tests, collected the data, drew Extended Data Figs. 7–9, recorded and edited the video and wrote the paper. A.A. designed the EEG experiment, collected and analyzed the data, drew Figs. 1 and 2 and wrote the paper. F.G. designed the software for the medical device and wrote the paper. J.N.M. and S.D.E. collected the data. A.D. designed the EEG experiment, collected and analyzed the data, drew Figs. 1 and 2 and wrote the paper. J-B.d.S.A. designed the EEG experiment, collected and analyzed the data, drew Figs. 1 and 2 and wrote the paper. C.d.M. designed and collected the data for the vision tests. E.G. designed the functional vision tests. I.A. collected and analyzed the data. J.D. contributed to the preclinical development. S.P. contributed to the preclinical development. D.D. contributed to the preclinical development and wrote the paper. L.B. analyzed the data, drew the figures and wrote the paper. M.T. supervised the study, monitored the safety data and wrote the paper. B.R. analyzed the data and wrote the paper.

Corresponding authors

Correspondence to José-Alain Sahel or Botond Roska.

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Competing interests

F.G., L.B. and M.T. are employees of GenSight Biologics. B.R. is the Chair of the Scientific Advisory Board of GenSight Biologics and is a board member of and has financial interest in Arctos Medical AG. J.-A.S. has personal financial interests in GenSight Biologics, Pixium Vision, SparingVision, Prophesee, Tilak, VegaVect, NewSight and Chronolife. E.B.-S. is a consultant for GenSight Biologics. D.D. was a consultant for GenSight Biologics, is a cofounder and acting Chief Strategy Officer of Gamut Tx. D.D. is an inventor on a patent of adeno-associated virus virions with variant capsid and methods of use thereof with royalties paid to Adverum (WO2012145601 A2). S.P. owns shares in, received consultant fees from and has filed a patent (WO 2017/187272) licensed to GenSight Biologics. S.P. has financial interests in Pixium Vision, Gamut, Iconeus, Chronolife, Neurallys and Prophesee. I.A. is a consultant for Novartis, Biogen and SparingVision and a cofounder of Gamut Tx. The other authors declare no competing interests.

Additional information

Peer review information Nature Medicine thanks Bart Leroy, Ione Fine and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Jerome Staal 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 Light-stimulating goggles.

a. GS030-MD consists of two units connected by a high-speed link. The head unit (left) hosts the camera which acquires the natural scene in a stream of asynchronous address-events representing pixel coordinates of local relative light intensity changes. The processing unit (right) encodes the visual stream in real time and creates binary images that are sent to the projector in the head unit. The projector, which is also mounted on the head unit (top), is placed in front of the eye. b. Front and rear view of the head unit. The camera is placed at the center facing the outside world. The projector is placed in front of the treated eye, facing the eye, and can be moved horizontally so as to be placed precisely in front of the treated eye’s pupil, since inter-pupillary distance varies between patients.

Extended Data Fig. 2 Timeline of protocol visits, visual training visits, and test visits.

a. Timeline of protocol visits. Each vertical line corresponds to a visit described in the clinical trial protocol. The visit (week (W) 0) at which the subject was injected is shown in green. The light-stimulating goggles were tested before injection on W-3,W-2, and W-1, shown in yellow. Protocol visits included ocular and general examinations. The time period at which visual training and the three visual tests occurred is shown in light blue. b. Timeline of visual training and visual test visits, which corresponds to the light blue region on a. Each dark blue line corresponds to a visual training visit (19 visits, thick lines indicate two closely spaced visits). Visual tests 1 and 2 were both run on the two visits shown in red, visual test 3 and EEG (electroencephalography) were run on the two visits shown in orange.

Extended Data Fig. 3 OCT imaging of the retina 4 weeks before injection.

OCT scans of the retina (location indicated by green arrow) taken 4 weeks before intravitreal injection of GS030-DP. Bilateral hyporeflective cyst-like spaces (shown in light-blue circles) are commonly found in late-stage RP and represent outer retinal degeneration.

Extended Data Fig. 4 OCT imaging of the retina 25 weeks after injection.

OCT scans of the retina (location indicated by green arrow) taken 25 weeks after intravitreal injection of GS030-DP. Bilateral hyporeflective cyst-like spaces (shown in light-blue circles) are commonly found in late-stage RP and represent outer retinal degeneration.

Extended Data Fig. 5 OCT imaging of the retina 52 weeks after injection.

OCT scans of the retina (location indicated by green arrow) taken 52 weeks after intravitreal injection of GS030-DP. Bilateral hyporeflective cyst-like spaces (shown in light-blue circles) are commonly found in late-stage RP and represent outer retinal degeneration.

Extended Data Fig. 6 OCT imaging of the retina 80 weeks after injection.

OCT scans of the retina (location indicated by green arrow) taken 80 weeks after intravitreal injection of GS030-DP. Only the treated eye was assessed on that visit. Hyporeflective cyst-like spaces (example shown in light-blue circle) are commonly found in late-stage RP and represent outer retinal degeneration.

Extended Data Fig. 7

Visual training program.

Extended Data Fig. 8 Schematic of vision test 1.

Test 1: perceiving, locating, and touching a single object. The subject had to perceive, locate, and touch a single object placed on a white table (80 cm × 80 cm; 67.2o × 50.9o visual angle) along an imaginary line at 40 cm from the subject (60 cm from the eyes of the subject), and 20 cm to the right or to the left (18.4o) or in front of the subject. The object was either a notebook (12.5 cm × 17.5 cm; 10.8o × 10.3o) or a staple box (3 cm × 5.5 cm; 2.8o × 3.7o), displayed individually in three different contrasts (Michelson contrasts 40%, 55%, and 100%; notebook: RMS contrasts 0.41, 0.53, 0.80; staple box: RMS contrasts 0.13, 0.16, 0.21) in a random order.

Extended Data Fig. 9 Schematic of vision test 2.

Test 2: perceiving, counting, and locating more than one object. The subject had to count and locate two or three tumblers placed on a white table (80 cm × 80 cm; 67.2° × 50.9° visual angle) and to point at them without touching. Tumblers (6 cm diameter and 6 cm height, 5.5° and 8.1° at 40 cm, 4.2° and 5.8° at 66 cm) were positioned at two or three of six possible positions along two imaginary lines: at 40 cm from the subject (60 cm from the eyes of the subject), and 20 cm to the right or to the left (18.4°) or in front of the subject; or at 66 cm from the subject (80 cm from the eyes of the subject), and 20 cm to the right or to the left (14°) or in front of the subject. The objects were displayed in three different contrasts (Michelson contrasts 40%, 55%, and 100%; RMS contrasts 0.29, 0.33, 0.41) in a random order.

Supplementary information

Supplementary Information

Supplementary Text.

Reporting Summary

Supplementary Video 1

Vision test 1: perceiving, locating and touching a single object. Test details are shown in Extended Data Fig. 8.

Supplementary Video 2

Vision test 2: perceiving, counting and locating more than one object. Test details are shown in Extended Data Fig. 9.

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Sahel, JA., Boulanger-Scemama, E., Pagot, C. et al. Partial recovery of visual function in a blind patient after optogenetic therapy. Nat Med 27, 1223–1229 (2021). https://doi.org/10.1038/s41591-021-01351-4

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