June 2020
Volume 61, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2020
Treatment Potential for LCA5-associated Leber Congenital Amaurosis
Author Affiliations & Notes
  • Katherine E. Uyhazi
    Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
    Perelman Center for Advanced Medicine at the Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Puya Aravand
    Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Brent A. Bell
    Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Zhangyong Wei
    Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Lanfranco Leo
    Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Leona Serrano
    Perelman Center for Advanced Medicine at the Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Denise J. Pearson
    Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
    Perelman Center for Advanced Medicine at the Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Ivan Shpylchak
    Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Jennifer Pham
    Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Vidyullatha Vasireddy
    Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Jean Bennett
    Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Tomas S Aleman
    Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
    Perelman Center for Advanced Medicine at the Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Katherine Uyhazi, None; Puya Aravand, None; Brent Bell, None; Zhangyong Wei, None; Lanfranco Leo, None; Leona Serrano, None; Denise Pearson, None; Ivan Shpylchak, None; Jennifer Pham, None; Vidyullatha Vasireddy, None; Jean Bennett, Gensight Biologics (S), Limelight Bio (F), Spark Therapeutics (P); Tomas Aleman, None
  • Footnotes
    Support  NIH/NEI Grant 5K12EY015398-14, Hope for Vision, The Foundation Fighting Blindness, Macula Vision Research Foundation, The Paul and Evanina Bell Mackall Foundation Trust, the Brenda and Matthew Shapiro Stewardship, the Robert and Susan Heidenberg Investigative Research Fund for Ocular Gene Therapy, The Pennsylvania Lions Sight Conservation and Research Foundation, and Research to Prevent Blindness
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 4500. doi:
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    • Get Citation

      Katherine E. Uyhazi, Puya Aravand, Brent A. Bell, Zhangyong Wei, Lanfranco Leo, Leona Serrano, Denise J. Pearson, Ivan Shpylchak, Jennifer Pham, Vidyullatha Vasireddy, Jean Bennett, Tomas S Aleman; Treatment Potential for LCA5-associated Leber Congenital Amaurosis. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4500.

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

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Abstract

Purpose : To determine the therapeutic window for gene replacement in inherited retinal degenerations caused by mutations in the gene encoding Lebercilin (LCA5).

Methods : Five patients (ages 6-31) with Leber congenital amaurosis (LCA) and biallelic LCA5 mutations underwent a complete ophthalmic exam including spectral domain optical coherence tomography (SD-OCT), full-field stimulus testing (FST) and pupillometry. In the Lca5gt/gt mouse model of the disease, the time course of photoreceptor degeneration and the efficacy of subretinal gene replacement therapy with AAV8-hLCA5 administered in early (P5), mid (P15), and late (P30) stage disease were assessed using SD-OCT, histology, electroretinography (ERG), and pupillometry. Comparisons were made with the human disease.

Results : Patients with LCA5 mutations have a maculopathy with detectable outer nuclear layer (ONL) in the pericentral retina and ~4 log units of sensitivity loss. The Lca5gt/gt mouse has a similarly severe and rapid photoreceptor degeneration. The ONL became progressively thinner and was undetectable by P60. Rod- and cone-mediated ERGs were severely reduced in amplitudes at P30 and became non-detectable by P60. Subretinal AAV8-hLCA5 administered to Lca5gt/gt mice at P5 and P15, but not at P30, resulted in structural and functional rescue.

Conclusions : LCA5-LCA is a particularly severe form of LCA that is recapitulated in the Lca5gt/gt mouse. Gene replacement results in structural and functional rescue in the Lca5gt/gt mouse if delivered before P30. Retained photoreceptors were visible within the central retina in all LCA5-LCA patients, in most at a level equivalent to that observed in rescued Lca5gt/gt mice, suggesting a window of opportunity for the treatment of LCA5-LCA patients.

This is a 2020 ARVO Annual Meeting abstract.

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