July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
The development of a therapy for retinitis pigmentosa based on the combined administration of the two products encoded by the nucleoredoxin like-1 gene
Author Affiliations & Notes
  • Emmanuelle Clerin
    Institut de la Vision, Paris, France
  • Ying Yang
    Institut de la Vision, Paris, France
  • Delphine Pagan
    Institut de la Vision, Paris, France
  • Seiki Achiedo
    Institut de la Vision, Paris, France
  • Julie Degardin
    Institut de la Vision, Paris, France
  • Quénol Cesar
    Institut de la Vision, Paris, France
  • Manuel Simonutti
    Institut de la Vision, Paris, France
  • Géraldine Millet-puel
    Institut de la Vision, Paris, France
  • Frédéric Blond
    Institut de la Vision, Paris, France
  • Najate Ait-Ali
    Institut de la Vision, Paris, France
  • José-Alain Sahel
    Institut de la Vision, Paris, France
  • Thierry Leveillard
    Institut de la Vision, Paris, France
  • Footnotes
    Commercial Relationships   Emmanuelle Clerin, Institut de la Vision (P); Ying Yang, None; Delphine Pagan, None; Seiki Achiedo, None; Julie Degardin, None; Quénol Cesar, None; Manuel Simonutti, None; Géraldine Millet-puel, None; Frédéric Blond, None; Najate Ait-Ali, None; José-Alain Sahel, Inserm Transfert (P), SparingVision (I); Thierry Leveillard, Inserm Transfert (P), SparingVision (C), SparingVision (I)
  • Footnotes
    Support  Inserm; Université Pierre et Marie Curie; Agence nationale pour la recherche; Foundation Fighting blindness
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 3963. doi:
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      Emmanuelle Clerin, Ying Yang, Delphine Pagan, Seiki Achiedo, Julie Degardin, Quénol Cesar, Manuel Simonutti, Géraldine Millet-puel, Frédéric Blond, Najate Ait-Ali, José-Alain Sahel, Thierry Leveillard; The development of a therapy for retinitis pigmentosa based on the combined administration of the two products encoded by the nucleoredoxin like-1 gene. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3963.

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

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Abstract

Purpose : Retinitis pigmentosa is an inherited retinal degeneration that processes from the death of rods followed by dysfunction and degeneration of cones. The nucleoredoxin-like 1 (NXNL1) gene encodes for two different proteins by alternative splicing: the trophic factor Rod-derived cone viability factor (RdCVF) and the long form, the thioredoxin (RdCVFL). RdCVF acts by stimulating aerobic glycolysis to sustain cone outer segment renewal and RdCVFL protects the cones against hyperoxia. In order to translate this promising therapy towards the clinic independently of the causative gene, we have evaluated the therapeutic benefit of delivering both products of the NXNL1 gene by subretinal injection with an AAV vector targeting retinal pigmented epithelial cells and cones in a mouse model of the disease.

Methods : Unilateral subretinal delivery of AAV-RdCVF/RdCVFL as compared to AAV-GFP and sham were performed in rd10 mice (7-9 animals per group) at 15 days post-natal. The visual acuity test was carried out from 30 days to 55 days post-natal. Eye fundus pictures are collected to control the GFP expression. Following the sacrifice of rd10 animals, eyes were collected and used for automated counting after the labelling of cones with peanut agglutinin using e-conome. The quality control of AAV particles was made by transmission electron microscopy and completed by silver staining gel electrophoretic analysis.

Results : The kinetics of the loss of visual acuity was statistically significantly retarded after injection of AAV-RdCVF-RdCVFL in 3 independent experiments. The results were validated by the increase of cone density. We have validated the quality of the viral productions by measuring the percentage full to empty particles using electron microscopy (90%). Poly-unsaturated fatty acids lipids of the external segment of photoreceptors are essential for phototransduction, prone to oxidation. We show a reduced amount of malondialdehyde (MDA), a marker of lipid peroxidation, in animals after the injection of AAV-RdCVF-RdCVFL compared to AAV-RdCVF demonstrating the additional protective effect of RdCVFL on cones, strengthening the interest to combine RdCVF and RdCVFL.

Conclusions : Our results demonstrate that this treatment will likely be successful in preserving central vision in patients suffering of retinitis pigmentosa in the near future.

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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