June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Gene therapy for Wnt signalling-related retinal detachment: Intravitreal injection of AAV.NDP is an effective treatment for vascular exudation in a mouse model of familial exudative vitreoretinopathy (FEVR)/ Coats disease
Author Affiliations & Notes
  • James Wawrzynski
    Institute of Child Health, University College London, London, London, United Kingdom
    Great Ormond Street Hospital for Children NHS Foundation Trust, London, London, United Kingdom
  • Robert Henderson
    Great Ormond Street Hospital for Children NHS Foundation Trust, London, London, United Kingdom
    Moorfields Eye Hospital NHS Foundation Trust, London, London, United Kingdom
  • Valda Pauzuolyte
    Institute of Child Health, University College London, London, London, United Kingdom
  • Aara Patel
    Institute of Child Health, University College London, London, London, United Kingdom
    Great Ormond Street Hospital for Children NHS Foundation Trust, London, London, United Kingdom
  • Oliver Coombe-Tennant
    Institute of Child Health, University College London, London, London, United Kingdom
  • Dale Moulding
    Institute of Child Health, University College London, London, London, United Kingdom
  • Jane C. Sowden
    Institute of Child Health, University College London, London, London, United Kingdom
  • Footnotes
    Commercial Relationships   James Wawrzynski University College London, Code P (Patent); Robert Henderson None; Valda Pauzuolyte University College London, Code P (Patent); Aara Patel University College London, Code P (Patent); Oliver Coombe-Tennant None; Dale Moulding None; Jane Sowden University College London, Code P (Patent)
  • Footnotes
    Support  Great Ormond Street Hospital Charity, VS0220
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 777. doi:
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      James Wawrzynski, Robert Henderson, Valda Pauzuolyte, Aara Patel, Oliver Coombe-Tennant, Dale Moulding, Jane C. Sowden; Gene therapy for Wnt signalling-related retinal detachment: Intravitreal injection of AAV.NDP is an effective treatment for vascular exudation in a mouse model of familial exudative vitreoretinopathy (FEVR)/ Coats disease. Invest. Ophthalmol. Vis. Sci. 2023;64(8):777.

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

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Abstract

Purpose : Development of the retinal vasculature and blood retinal barrier (BRB) depends on canonical Wnt signalling. Pathogenic variants in constituents of this pathway (eg. NDP or TSPAN12) may result in poorly developed retinal vasculature and thus congenital tractional retinal detachment or exudative detachment in childhood.

We tested the hypotheses that:

AAV(ShH10).NDP gene therapy restores normal retinal vascularisation and reinstates the integrity of the BRB in an Ndp KO mouse model of FEVR/ Coats disease

Our NDP gene therapy construct activates WNT signalling in the absence of the co-receptor TSPAN12 in a HEK cell model

Methods : Ndp KO mice received an intravitreal injection of either AAV(ShH10).NDP or vehicle at either p8 (during retinal vascular development) or p22 (after development is complete). Groups of 6 treated/ 6 control eyes were compared at p30/p45. Outcome measures were: Density of vascularisation (retinal wholemounts), presence of retinal capillaries (cryosection), electroretinogram b wave height(ERG), integrity of BRB (functional assay of AF594 tagged albumin accumulation/ expression of BRB constituents on cryosection)

Wnt signalling in response to our NDP construct was also quantified by topflash assay in HEK cells

ANOVA and Kruskal–Wallis tests were used

Results : AAV(ShH10).NDP at p8 rescued the retinal vascular architecture, ERG and fully restored the BRB, n=6, p<0.05. Treatment at p22 did not rescue the retinal vascular architecture or ERG but did largely restore the BRB structure (claudin-5 present, PLVAP absent in vascular endothelial cells) and function (WT:5.29, KO:100, treated KO:40.94 ng albumin-AF594 per mg retina, KO vs treated KO p<0.05)

In HEK cells our NDP construct was able to stimulate Wnt signalling in the presence of its receptor complex with or without the addition of the co-receptor TSPAN12

Conclusions : Intravitreal AAV(ShH10).NDP can restore retinal vascular architecture and the BRB in a mouse model of FEVR/ Coats disease if treatment is delivered during retinal vascular development. The BRB can still be partially rescued even once retinal vascular development is complete. The latter finding potentially establishes a therapeutic window for the treatment of exudative retinal detachment in NDP or TSPAN-12 related FEVR or Coats disease in childhood.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

 

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