June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Gene therapy rescues cone function in rhesus macaques with PDE6C cone disorder
Author Affiliations & Notes
  • Ala Moshiri
    Ophthalmology, University of California Davis, Davis, California, United States
  • Tawfik Issa
    Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, United States
  • Antonio Lopez
    Ophthalmology, University of California Davis, Davis, California, United States
  • Sangwan Park
    Surgical & Radiological Sciences, University of California Davis, Davis, California, United States
  • Jeffrey Rogers
    Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States
    Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
  • Rui Chen
    Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
    Biochemistry & Molecular Biology, Baylor College of Medicine, Houston, Texas, United States
  • Eliza Bliss-Moreau
    Psychology, California National Primate Research Center, University of California Davis, Davis, California, United States
  • Sara M Thomasy
    Surgical & Radiological Sciences, University of California Davis, Davis, California, United States
    Ophthalmology, University of California Davis, Davis, California, United States
  • Tim Stout
    Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, United States
  • Footnotes
    Commercial Relationships   Ala Moshiri None; Tawfik Issa None; Antonio Lopez None; Sangwan Park None; Jeffrey Rogers None; Rui Chen None; Eliza Bliss-Moreau None; Sara Thomasy None; Tim Stout None
  • Footnotes
    Support  NIH U24 EY029904, NIH K08 EY27463
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 1114. doi:
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    • Get Citation

      Ala Moshiri, Tawfik Issa, Antonio Lopez, Sangwan Park, Jeffrey Rogers, Rui Chen, Eliza Bliss-Moreau, Sara M Thomasy, Tim Stout; Gene therapy rescues cone function in rhesus macaques with PDE6C cone disorder. Invest. Ophthalmol. Vis. Sci. 2022;63(7):1114.

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

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Abstract

Purpose : To determine the age of disease onset and the degree to which viral mediated gene therapy can rescue cone function in a nonhuman primate model of an inherited cone disorder.

Methods : Infant rhesus macaques homozygous for the PDE6C R565Q mutation were generated through a selective breeding program at the California National Primate Research Center (CNPRC). Their genotypes were confirmed by genetic sequencing in the first few months of life. At age 9 months, two of the homozygous animals were treated in the right eye with either a high (1.5 x 1011 vg/eye) or low (1.5 x 1010 vg/eye) dose of adeno-associated virus (AAV5) carrying the rhesus macaque PDE6C gene under the control of the PR1.7 cone-specific promoter. The left eye was used as a control. Animals were tested in each eye by full-field and multifocal electroretinography (ERG) before and after injection. Behavioral testing was performed to assess visual acuity and color perception.

Results : All offspring homozygous for the PDE6C R565Q mutation had an absent cone signal and foveal autofluorescence abnormalities from early infancy. Subretinal injection in infant macaques was successfully accomplished. The virus was given along with systemic corticosteroids and was found to be safe without significant inflammation or toxicity. There were no obvious alterations in retinal lamination or cell loss in treated eyes. The therapeutic virus transduced retinal cells very efficiently and was expressed specifically in cone photoreceptors. Eyes treated with the high dose of the virus exhibited mild inflammation that was controlled with corticosteroids. The high dose restored cone responses on ERG within one month of injection. The responses were sustained and durable for at least 6 months without evidence of decline. Chromatic ERG testing showed restoration of amplitudes in all three cone subtypes. Behavioral testing to assess visual acuity and color perception is in progress.

Conclusions : AAV-mediated gene therapy for PDE6C was safe in the nonhuman primate model. It effectively restored cone function in all cone subtypes. Treated animals had durable restoration of the cone signal on ERG. These results suggest similar approaches in human patients may warrant investigation.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

 

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