April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
A mouse model to assess gene therapy for RLBP1-associated retinal dystrophy
Author Affiliations & Notes
  • Chad E Bigelow
    Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, MA
  • Shawn M Hanks
    Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, MA
  • Joanna Vrouvlianis
    Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, MA
  • Oliver Turner
    Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, NJ
  • Gregory Argentieri
    Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, NJ
  • George Bounoutas
    Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, MA
  • Vivian W Choi
    Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, MA
  • Thaddeus P Dryja
    Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, MA
  • Seshidhar Reddy Police
    Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, MA
  • Bruce D Jaffee
    Ophthalmology, Novartis Institutes for BioMedical Research, Cambridge, MA
  • Footnotes
    Commercial Relationships Chad Bigelow, Novartis Institutes for BioMedical Research (E); Shawn Hanks, Novartis Institutes for BioMedical Research (E); Joanna Vrouvlianis, Novartis Institutes for BioMedical Research (E); Oliver Turner, Novartis Institutes for BioMedical Research (E); Gregory Argentieri, Novartis Institutes for BioMedical Research (E); George Bounoutas, Novartis Institutes for BioMedical Research (E); Vivian Choi, Novartis Institutes for BioMedical Research (E); Thaddeus Dryja, Novartis Institutes for BioMedical Research (E); Seshidhar Reddy Police, Novartis Institutes for BioMedical Research (E); Bruce Jaffee, Novartis Institutes for BioMedical Research (E)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 1640. doi:
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      Chad E Bigelow, Shawn M Hanks, Joanna Vrouvlianis, Oliver Turner, Gregory Argentieri, George Bounoutas, Vivian W Choi, Thaddeus P Dryja, Seshidhar Reddy Police, Bruce D Jaffee; A mouse model to assess gene therapy for RLBP1-associated retinal dystrophy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1640.

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

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Abstract

Purpose: To develop a mouse model to test recombinant adeno-associated viral (rAAV) vectors for RLBP1 gene delivery to the eye.

Methods: Retinal morphology was evaluated in RLBP1+/+ and RLBP1-/- mice of 4, 10, and 16 months of age. Assessments were made by viewing sections stained with hematoxylin and eosin or by using image processing on a subset of the sections to determine retina and outer nuclear layer thickness. Dark-adapted electroretinograms (ERGs) were used to assess photoreceptor function in RLBP1+/+, RLBP1+/-, and RLBP1-/- mice. Dark-adapted photoreceptor function was compared between genotypes using a 15-step intensity response series (-1.0 to 3.7 log scot cd s m-2). The rate of dark adaptation was assessed by monitoring ERG a-wave amplitude recovery after a photobleach (16 xenon flashes: 3.7 log scot cd s m-2). In order to test the ability of gene delivery to restore visual function to RLBP1-/- mice, 3.6x108 vg/eye of AAV-pRLBP1-hRLBP1 vectors (NVS1 or NVS2) with different serotypes were injected subretinally. 12 weeks post-injection, recovery of a-wave amplitude (dark adaptation) 4 hours post-bleach was measured.

Results: There were no notable differences in retinal morphology with age or between genotypes based on light microscopy examination or image processing. Dark-adapted photoreceptor function was also indistinguishable between genotypes. However, slow dark adaptation was observed in RLBP1-/- mice compared to wild-type or heterozygous controls. RLBP1+/+, RLBP1+/-, and RLBP1-/- groups at ~3 hours post-bleach exhibited a-wave recoveries of 89%, 97%, and 14%, respectively. Subretinal delivery of NVS1 or NVS2 increased the rate of dark adaptation in RLBP1-/- mice. Four hours post-photobleach, naïve eyes recovered 13% of a-wave amplitude compared to 38% (p<0.01) and 87% (p<0.001) for those receiving NVS1 or NVS2, respectively. Serotype-related efficacy differences were significant: eyes that received NVS2 exhibited a >2-fold increase in a-wave amplitude 4 hours post-bleach vs. those receiving NVS1 (p<0.001).

Conclusions: RLBP1-/- mice exhibit slow dark adaptation that is similar to the deficit observed in patients with RLBP1-associated retinal dystrophy. ERG-based assessments in this model indicate that the rate of dark adaptation can be substantially improved with viral vector-mediated gene delivery and that the assay possesses sufficient sensitivity to differentiate viral vectors with different properties.

Keywords: 510 electroretinography: non-clinical • 538 gene transfer/gene therapy  
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