June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Gene augmentation therapy in a large animal model of PDE6A-Retinitis Pigmentosa results in functional and structural rescue for at least 2.5 years.
Author Affiliations & Notes
  • Laurence Mireille Occelli
    Small Animal Clinical Sciences, Michigan State University, East Lansing, Michigan, United States
  • Stylianos Michalakis
    Department of Pharmacy – Center for Drug Research, Ludwig-Maximilians-Universität München, Munich, Germany
    Department of Ophthalmology, Ludwig-Maximilians-Universität München, Munich, Germany
  • Martin Biel
    Department of Ophthalmology, Ludwig-Maximilians-Universität München, Munich, Germany
  • consortium RD-Cure
    Department of Ophthalmology, Ludwig-Maximilians-Universität München, Munich, Germany
  • Simon M Petersen-Jones
    Small Animal Clinical Sciences, Michigan State University, East Lansing, Michigan, United States
  • Footnotes
    Commercial Relationships   Laurence Occelli, None; Stylianos Michalakis, PCT/EP2017/054230 (P); Martin Biel, PCT/EP2017/054230 (P); consortium RD-Cure, None; Simon Petersen-Jones, None
  • Footnotes
    Support  Myers-Dunlap Endowment for Canine Health, RD-Cure consortium and Tistou & Charlotte Kerstsan Stiflung
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 1913. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Laurence Mireille Occelli, Stylianos Michalakis, Martin Biel, consortium RD-Cure, Simon M Petersen-Jones; Gene augmentation therapy in a large animal model of PDE6A-Retinitis Pigmentosa results in functional and structural rescue for at least 2.5 years.. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1913.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose : PDE6A is an essential subunit of the PDE6 holoenzyme which is necessary for rod phototransduction. Mutations in PDE6A cause retinitis pigmentosa type 43. A spontaneous dog model with a loss of function mutation in Pde6a shows a failure of rod phototransduction, accumulation of cGMP, rapid rod cell death followed by a secondary loss of cones. We previously showed rescue of the dog phenotype using an adeno-associated virus (AAV) vector delivering the human PDE6A cDNA. This current study aims to report the long-term outcome of this therapy.

Methods : Four 27 day old Pde6a-/- puppies were treated with a subretinal injection of an AAV vector serotype 8 delivering human PDE6A cDNA under control of a rhodopsin promoter (AAV8-hPDE6A) at a 5x1011 vector genomes dose. The rescue obtained up to 4 months post injection has been reported (Occelli et al 2017). These dogs have now been followed up to 2.5 years post injection. Functional rescue was monitored by vision testing (VT) and electroretinography (ERG), and structural preservation by spectral domain-optical coherence tomography (SD-OCT) and retinal vessel preservation by OCT-angiography.

Results : Excellent rescue of rod function as assessed by VT and ERG was maintained for the duration of the study. VT also showed that the treatment preserved cone-mediated vision that over this time period became markedly impaired in the untreated eyes. This preservation of cone function was confirmed by light-adapted ERGs. Structural preservation, only within the treated retinal areas, was maintained over the 2.5 year period. The treated regions showed normal layer morphology and preserved layer thicknesses with the zones representing the photoreceptor inner and outer segments clearly visible. In comparison, the untreated areas showed advanced retinal thinning with loss of discernable layer morphology. Preservation of the retinal vasculature in the treated regions was striking compared to the untreated retinal regions.

Conclusions : This study shows that early gene augmentation therapy in Pde6a-/- dogs can result in maintenance of a normal appearing and functional retina in the treated region for at least 2.5 years. Importantly function of both rods and cones is maintained, as well as retinal structure and blood supply. This positive outcome with a translatable vector is an important step towards a human clinical trial.

This is a 2020 ARVO Annual Meeting abstract.

×
×

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.

×