March 2012
Volume 53, Issue 14
ARVO Annual Meeting Abstract  |   March 2012
Evaluation Of Eye Physiopathology In The Harlequin Mouse Strain Aimed At Developing A Gene Therapy Based On A Permanent Mitochondrial Function Protection
Author Affiliations & Notes
  • Aicha Bouaita
    Institut de la Vision, Paris, France
  • Sébastien Augustin
    Institut de la Vision, Paris, France
  • Christophe Lechauve
    Institut de la Vision, Paris, France
  • Hélène Cwerman-Thibault
    Institut de la Vision, Paris, France
  • Hong Liang
    Institut de la Vision, Paris, France
  • Françoise Brignole-Baudouin
    Institut de la Vision, Paris, France
  • José-Alain SAHEL
    Institut de la Vision, Paris, France
  • Marisol Corral-Debrinski
    Institut de la Vision, Paris, France
  • Footnotes
    Commercial Relationships  Aicha Bouaita, None; Sébastien Augustin, None; Christophe Lechauve, None; Hélène Cwerman-Thibault, None; Hong Liang, None; Françoise Brignole-Baudouin, None; José-Alain Sahel, None; Marisol Corral-Debrinski, None
  • Footnotes
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 1894. doi:
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      Aicha Bouaita, Sébastien Augustin, Christophe Lechauve, Hélène Cwerman-Thibault, Hong Liang, Françoise Brignole-Baudouin, José-Alain SAHEL, Marisol Corral-Debrinski; Evaluation Of Eye Physiopathology In The Harlequin Mouse Strain Aimed At Developing A Gene Therapy Based On A Permanent Mitochondrial Function Protection. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1894.

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

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Purpose: : The Harlequin (Hq) mutant mouse, characterized by the depletion of the mitochondrial Apoptosis Inducing Factor (AIF), represents a genetic model that resembles human pathologies caused by respiratory chain complex I deficiency. These mice exhibits photoreceptor and retinal ganglion cell (RGC) loss. We demonstrated that RGC loss and complex I deficiency in optic nerves were durably prevented by AAV2-AIF administration. Hence, our next objective was to shed light on abnormalities in retinas and anterior eye segments, the extent of cell dysfunction and the kinetics of their appearance for at last, develop a gene therapy for preventing eye pathology in Hq mice.

Methods: : We have performed in vivo imaging of eye structures, electroretinograms (ERG) and immunochemistry studies. Besides, mitochondrial respiratory chain complex activities in retinas and optic nerves were determined by spectrometric assessments.

Results: : Hq mice display abnormalities in the cornea, for instance the presence of large superficial and hyper-reflective epithelial cells and outsized multinucleated cells in the stroma. In some mice epithelium invaginations through the stroma were obvious as well as neovascularisation. Photoreceptor loss was apparent in Hq mice aged 6 months. In animals 12-month old, the retinal thickness was 2-fold reduced as compared to controls. Functional assessment performed by ERG recordings in mice 6-month old did show a significant decrease in scotopic and photopic function; at 9 months the average amplitude of scotopic and photopic ERG B-wave amplitudes were reduced by 95% relative to age-matched controls. All these structural and functional changes were associated with a significant complex I deficiency in Hq retinas relative to age- matched controls (a 70% reduction in its enzymatic activity in mice older than 8 months).

Conclusions: : Since we determined the kinetics of photoreceptor and corneal cell loss, we designed an approach based on optimized gene expression (co-translational import of the therapeutic protein by targeting the mRNA to the mitochondrial surface) to prevent visual loss in Hq mice. We expect that subretinal or intracameral administration of AAV2-AIF in 2-3 month old mice will preserve cell integrity and prevent complex I defect.

Keywords: retina: proximal (bipolar, amacrine, and ganglion cells) • retina: distal (photoreceptors, horizontal cells, bipolar cells) • anterior segment 

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