Format

Send to

Choose Destination
Mol Ther. 2018 Jan 3;26(1):219-237. doi: 10.1016/j.ymthe.2017.09.007. Epub 2017 Sep 8.

Otx2-Genetically Modified Retinal Pigment Epithelial Cells Rescue Photoreceptors after Transplantation.

Author information

1
INSERM, U968, Paris 75012, France; Sorbonne Universités, UPMC Univ Paris 06 UMR_S 968, Institut de la Vision, Paris 75012, France; CNRS, UMR_7210, Paris 75012, France.
2
INSERM, U968, Paris 75012, France; Sorbonne Universités, UPMC Univ Paris 06 UMR_S 968, Institut de la Vision, Paris 75012, France; CNRS, UMR_7210, Paris 75012, France; Unité Rétine, Uvéite et Neuro-Ophtalmologie, Département d'Ophtalmologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
3
INSERM, U968, Paris 75012, France; Sorbonne Universités, UPMC Univ Paris 06 UMR_S 968, Institut de la Vision, Paris 75012, France; CNRS, UMR_7210, Paris 75012, France. Electronic address: thierry.leveillard@inserm.fr.

Abstract

Inherited retinal degenerations are blinding diseases characterized by the loss of photoreceptors. Their extreme genetic heterogeneity complicates treatment by gene therapy. This has motivated broader strategies for transplantation of healthy retinal pigmented epithelium to protect photoreceptors independently of the gene causing the disease. The limited clinical benefit for visual function reported up to now is mainly due to dedifferentiation of the transplanted cells that undergo an epithelial-mesenchymal transition. We have studied this mechanism in vitro and revealed the role of the homeogene OTX2 in preventing dedifferentiation through the regulation of target genes. We have overexpressed OTX2 in retinal pigmented epithelial cells before their transplantation in the eye of a model of retinitis pigmentosa carrying a mutation in Mertk, a gene specifically expressed by retinal pigmented epithelial cells. OTX2 increases significantly the protection of photoreceptors as seen by histological and functional analyses. We observed that the beneficial effect of OTX2 is non-cell autonomous, and it is at least partly mediated by unidentified trophic factors. Transplantation of OTX2-genetically modified cells may be medically effective for other retinal diseases involving the retinal pigmented epithelium as age-related macular degeneration.

KEYWORDS:

KIR7.1; RCS rats; SLC16A8; adeno-associated virus; age-related macular degeneration; epithelial-mesenchymal transition; gene therapy; induced pluripotent stem-derived cells; neurotrophic factor; retinitis pigmentosa

PMID:
28988713
PMCID:
PMC5762984
DOI:
10.1016/j.ymthe.2017.09.007
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center