September 2021
Volume 21, Issue 9
Open Access
Vision Sciences Society Annual Meeting Abstract  |   September 2021
A demonstration of cone function plasticity after gene therapy in achromatopsia
Author Affiliations & Notes
  • Mahtab Farahbakhsh
    University College London, London, UK
  • Elaine J. Anderson
    University College London, London, UK
  • Andy Rider
    University College London, London, UK
  • John A. Greenwood
    University College London, London, UK
  • Nashila Hirji
    University College London, London, UK
    Moorfields Eye Hospital, London, UK
  • Serena Zaman
    University College London, London, UK
    Moorfields Eye Hospital, London, UK
  • Pete R. Jones
    University College London, London, UK
    City University, London, UK
  • D. Samuel Schwarzkopf
    University College London, London, UK
    University of Auckland, NZ
  • Geraint Rees
    University College London, London, UK
  • Michel Michaelides
    University College London, London, UK
    Moorfields Eye Hospital, London, UK
  • Tessa M. Dekker
    University College London, London, UK
  • Footnotes
    Acknowledgements  NIHR BRC at Moorfields Eye Hospital (MEH) and UCL Institute of Ophthalmology, ESRC, MeiraGTx, Retina UK, MEH Special Trustees, Moorfields Eye Charity, Foundation Fighting Blindness, Wellcome Trust, Ardalan Family Scholarship, Maryam Mirzakhani Scholarship, Sir Richard Stapley Educational Trust.
Journal of Vision September 2021, Vol.21, 2444. doi:https://doi.org/10.1167/jov.21.9.2444
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      Mahtab Farahbakhsh, Elaine J. Anderson, Andy Rider, John A. Greenwood, Nashila Hirji, Serena Zaman, Pete R. Jones, D. Samuel Schwarzkopf, Geraint Rees, Michel Michaelides, Tessa M. Dekker; A demonstration of cone function plasticity after gene therapy in achromatopsia. Journal of Vision 2021;21(9):2444. doi: https://doi.org/10.1167/jov.21.9.2444.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Achromatopsia (ACHM) is an inherited retinal disease characterised by complete loss of cone photoreceptor function from birth. In recent years, gene therapies have successfully been used to induce signal processing in dormant cones in animal models of ACHM, with greater functional benefits for younger animals. With several completed or on-going clinical trials of gene therapy for ACHM, preliminary evidence suggests that effects on visual function in adults with ACHM may be subtle. Given the known constraints of age on neural plasticity, it is possible that gene therapy earlier in life will have a greater impact. Sensitive, child-friendly tests of cone function are therefore needed to facilitate the optimisation of these treatment strategies. Here, we present a new method that leverages a multimodal approach, linking psychophysical estimates of cone function to cone-mediated signals in visual cortex, measured using fMRI population receptive field (pRF) mapping. To selectively stimulate rod and cone photoreceptors, we used silent substitution. In a case study of two children with ACHM undergoing gene therapy, we find individual differences in recovery of cone function over time. Before treatment, measures from both patients resembled those of 10 other untreated ACHM patients. After gene therapy, one patient demonstrated strong concurrent evidence of improved cone function, and retinotopically organised responses in visual cortex (V1-3) to cone-selective stimuli, with measures closely resembling those of 26 age-matched controls. Head motion, fixation stability, and task performance were very similar before and after treatment, so it is highly unlikely that these results are driven by measurement confounds. We conclude that our multimodal approach is feasible for use in children with low vision. Our fMRI and psychophysical measures show significant potential not only for sensitive evaluation of new sight-rescuing therapies, but also for revealing the neural mechanisms based on which these treatments operate in the developing brain.

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