July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Long-term preservation of photoreceptor function and structure following early-stage treatment by AAV-mediated gene augmentation in canine model of NPHP5 Leber congenital amaurosis
Author Affiliations & Notes
  • Gustavo D Aguirre
    Clinical Studies, Univ of Penn Sch Veterinary Med, Philadelphia, Pennsylvania, United States
  • Artur V Cideciyan
    Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Sanford L Boye
    Ophthalmology, University of Florida, Gainesville, Florida, United States
  • Simone Iwabe
    Clinical Studies, Univ of Penn Sch Veterinary Med, Philadelphia, Pennsylvania, United States
  • Valerie Dufour
    Clinical Studies, Univ of Penn Sch Veterinary Med, Philadelphia, Pennsylvania, United States
  • Malgorzata Swider
    Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Karolina Roszak
    Clinical Studies, Univ of Penn Sch Veterinary Med, Philadelphia, Pennsylvania, United States
  • William W Hauswirth
    Ophthalmology, University of Florida, Gainesville, Florida, United States
  • Samuel G Jacobson
    Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • William A Beltran
    Clinical Studies, Univ of Penn Sch Veterinary Med, Philadelphia, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Gustavo Aguirre, Provisional (P); Artur Cideciyan, Provisional (P); Sanford Boye, Provisional (P); Simone Iwabe, None; Valerie Dufour, None; Malgorzata Swider, None; Karolina Roszak, None; William Hauswirth, AGTC (I); Samuel Jacobson, Provisional (P); William Beltran, Provisional (P)
  • Footnotes
    Support  NIH EY-06855, -17549, -022012, -023937, -021721, Foundation Fighting Blindness, Macula Vision Research Foundation, Van Sloun Fund for Canine Genetic Research, Hope for Vision
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 6006. doi:
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      Gustavo D Aguirre, Artur V Cideciyan, Sanford L Boye, Simone Iwabe, Valerie Dufour, Malgorzata Swider, Karolina Roszak, William W Hauswirth, Samuel G Jacobson, William A Beltran; Long-term preservation of photoreceptor function and structure following early-stage treatment by AAV-mediated gene augmentation in canine model of NPHP5 Leber congenital amaurosis. Invest. Ophthalmol. Vis. Sci. 2018;59(9):6006.

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

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Abstract

Purpose : A C-terminal truncation of NPHP5 (IQCB1) causes a photoreceptor ciliopathy with an early onset, rapidly progressive retinal degeneration in dogs. By 6 wks of age, rod responses are markedly reduced in amplitude or absent, and cone responses are not recordable. The absence of cone function correlates with the lack of cone outer segments even though there is preservation of cone inner segments which offers the possibility for successful gene therapy. We now report on long-term efficacy of early-stage treatment.

Methods : Subretinal injections of 70 µl of cNPHP5 therapeutic vectors, AAV2/5-hIRBP- or scAAV2/8 (Y733F)-hGRK1-, at titers ranging from 1.5 – 5 E11 or E12 vg/ml were made into one eye of affected dogs at 5-6 wks of age, with fellow eyes serving as untreated controls. Photoreceptor structure and function were quantified by sdOCT and full-field ERGs. Visual behavior was assessed after ~ 1 yr following treatment using an obstacle avoidance course to separately test the treated and contralateral control eyes.

Results : Gene therapy restored cone function and improved rod function within 6-7 wks after treatment, and there were no treatment related complications. Post treatment functional evaluation showed sustained preservation of ERG rod and cone function for time periods ranging from 1.4 to 2.7 yrs after therapy. Testing in an obstacle avoidance course under scotopic and photopic illumination showed retained functional vision in the treated eyes under all illumination conditions. Treatment blebs were associated with significantly retained photoreceptor layer which was robust with better ONL preservation at the higher vector concentrations.

Conclusions : In spite of the very severe and rapidly progressive photoreceptor degeneration in NPHP5-LCA affected dogs, AAV-mediated gene augmentation restores rod and cone function, preserves vision and photoreceptor structure for time periods greater than 1.4-2.7 years without any deleterious effects. As the extent of photoreceptor disease is quite severe and advanced at the time of early-stage treatment, the results augur well for future translational applications.

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

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