September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
rAAV-mediated gene augmentation improves retinal and visual function and retinal structure in a mouse model for LCA5
Author Affiliations & Notes
  • Ji Yun Song
    Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Puya Aravand
    Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Ilan McNamara
    Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Junwei Sun
    Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Arkady Lyubarsky
    Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Jean Bennett
    Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Ji Yun Song, None; Puya Aravand, None; Ilan McNamara, None; Junwei Sun, None; Arkady Lyubarsky, None; Jean Bennett, Astellas Pharmaceuticals (C), Avalanche Biotechnologies (S), GenSight Therapeutics (C)
  • Footnotes
    Support  This work was carried out as a collaboration with the LCA5 consortium, which includes Frans Cremers, Anneke van den Hollander, Rob Koenekoop, Ronald Roepman, Patsy Nishina, Gerald Chader, Jeannette Bennicelli. Funding: NIH 8 DP1 EY023177, P30 EY001583, CHOP-Penn Center for Pediatric Retinal Degenerations, Research to Prevent Blindness, the Paul and Evanina Mackall Foundation Trust, the F.M. Kirby Foundation
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 5151. doi:
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      Ji Yun Song, Puya Aravand, Ilan McNamara, Junwei Sun, Arkady Lyubarsky, Jean Bennett; rAAV-mediated gene augmentation improves retinal and visual function and retinal structure in a mouse model for LCA5. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5151.

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

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Abstract

Purpose : Mutations in the gene encoding the ciliary protein lebercilin result in defects in intraflagellar trafficking (IFT) and cause a severe, childhood onset retinal degeneration known as Leber’s congenital amaurosis 5 (LCA5). The human condition is modeled in an engineered mouse model (Boldt et al, JCI 121:2169 (2011)). We tested the hypothesis that delivery of the wildtype human LCA5 cDNA would ameliorate the phenotype in this model.

Methods : The wildtype human LCA5 cDNA was delivered unilaterally to the eyes of neonatal Lca5-/- mice using AAV9 or AAV7m8 (1ul of 9.3E12-1.47E13 vg/ml virus per eye). AAV9 was delivered subretinally and AAV7m8 was delivered intravitreally. Contralateral eyes were untreated and used as internal controls. Untreated but punctured littermates were used as additional controls. Retinal and visual function was assessed by pupillometry (1000 and 3000 scot lux 5 ms stimuli) and by a water maze test (luminance of LED light source identifying the escape platform was 6E4 and 3E2 scot cd m-2 for training and testing respectively). Structural effects were evaluated by retinal histology.

Results : In 46 out of 49 treated mice, pupillometry revealed an increased pupil response in the treated eye as compared to the control one. In the water maze 40 out of 44 treated mice but only 2 out of 22 controls passed the test (p<0.001 by Fisher exact test). Histological analysis confirmed a greater number of retained photoreceptor cells in treated retinas as compared to controls.

Conclusions : Gene augmentation therapy with rAAV vectors rescues retinal structure and function in a mouse model of LCA5.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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