July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
AAV-mediated expression of X-linked Inhibitor of Apoptosis protects photoreceptors in two canine models of early onset RP
Author Affiliations & Notes
  • William A Beltran
    Division of Experimental Retinal Therapies, Dept. of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Artur V Cideciyan
    Dept. of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Simone Iwabe
    Division of Experimental Retinal Therapies, Dept. of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Valerie Dufour
    Division of Experimental Retinal Therapies, Dept. of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Jason Charng
    Dept. of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Brianna Lisi
    Dept. of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Jose-Manuel Guzman
    Division of Experimental Retinal Therapies, Dept. of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Alireza Badiei
    Division of Experimental Retinal Therapies, Dept. of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Catherine Tsilfidis
    Dept. of Ophthalmology, University of Ottawa, Ottawa, Ontario, Canada
  • William W Hauswirth
    Dept. of Ophthalmology, University of Florida, Gainesville, Florida, United States
  • Samuel G Jacobson
    Dept. of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Gustavo D Aguirre
    Division of Experimental Retinal Therapies, Dept. of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   William Beltran, None; Artur Cideciyan, None; Simone Iwabe, None; Valerie Dufour, None; Jason Charng, None; Brianna Lisi, None; Jose-Manuel Guzman, None; Alireza Badiei, None; Catherine Tsilfidis, None; William Hauswirth, None; Samuel Jacobson, None; Gustavo Aguirre, None
  • Footnotes
    Support  NIH EY-06855, -17549, the Foundation Fighting Blindness, the Van Sloun Fund for Canine Genetic Research.
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 4527. doi:https://doi.org/
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      William A Beltran, Artur V Cideciyan, Simone Iwabe, Valerie Dufour, Jason Charng, Brianna Lisi, Jose-Manuel Guzman, Alireza Badiei, Catherine Tsilfidis, William W Hauswirth, Samuel G Jacobson, Gustavo D Aguirre; AAV-mediated expression of X-linked Inhibitor of Apoptosis protects photoreceptors in two canine models of early onset RP. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4527. doi: https://doi.org/.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose : Overexpression of X-linked Inhibitor of Apoptosis (XIAP) has been shown to protect photoreceptors in rodent models of retinal degeneration. Here we evaluated the neuroprotective effect of AAV-mediated subretinal delivery of XIAP in two canine models of early onset RP: the rcd1 (PDE6B mutation) and XLPRA2 (RPGR mutation) dogs.

Methods : Subretinal injections of an AAV2/5-CBA-XIAP-WPRE vector (vol: 60-150 µl; titer: 4.8 x1011 vg/mL) were performed at early stage disease (~ 5.5 wks of age) in 6 rcd1 and 4 XLPRA2 eyes, and at mid-stage disease (11.1 wks of age) in 3 XLPRA2 eyes. ONL thickness was examined in the bleb areas by sdOCT and/or histology and compared to untreated areas of the same eye or to contralateral eyes that were sham-injected or uninjected. Photoreceptor function was assessed in XLPRA2 dogs by full-field ERGs.

Results : At 9 wks post-injection a significantly thicker ONL was observed by sdOCT in the treated area of all 6 rcd1 eyes injected with AAV-XIAP. Histology showed an ONL with a mean thickness of 4.5 (±0.8) rows of nuclei in the treated areas versus 2.7 (± 0.4) in untreated/ctrl areas. XLPRA2 dogs treated at early stage showed by sdOCT a significantly thicker ONL in the treated area both at 10 and 19 wks post injection; however rod-mediated ERG function was severely impaired in both AAV-XIAP and sham-injected eyes at 19 wks post injection. In XLPRA2 eyes injected with AAV-XIAP at mid-stage disease, photoreceptor loss was also reduced with treated areas showing thicker ONL by sdOCT than contralateral sham-injected eyes both at 8 and 13 wks post-injection. No rescue of rod-mediated ERG function was observed.

Conclusions : XIAP gene augmentation slows the course of photoreceptor death in two non-allelic canine models of RP. Increased survival of photoreceptors was not associated with improved rod function in the RPGR ciliopathy. These results suggest that AAV-XIAP gene therapy may provide a way of delaying loss of rods in RP and thus secondarily promoting cone survival and longer retention of cone-mediated vision.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×