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Yi-Sheng Chang, Winnette McIntosh Ambrose, Chris Lin, Haohua Qian, Tiansen Li, Tiziana Cogliati, Anand Swaroop; Cell-based Therapy In A Mouse Model Of Leber Congenital Amaurosis. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5841.
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Mutations in CEP290 are responsible for almost 25% of Leber congenital amaurosis (LCA). We have recently described the rd16/Nrl-/- mouse model that exhibits similarity to patients with CEP290-LCA (Cideciyan et al. Hum Mol Genet. 20:1411-1423, 2011). The goal of this project is to investigate the therapeutic effect of retinal cells transplanted into the degenerating retina from this cone-only mouse model.
Cells were dissociated from whole retina of the wild-type Nrl-GFP mice at postnatal day 3-5, and then transplanted into the cone-only degenerating retina of rd16/Nrl-/- mice at P14 by subretinal injection. Fundus photography, histology, immunohistochemistry and electroretinogram (ERG) were used for assessing the morphology and retinal function.
White dots on the retina and pseudorosettes (whorls) on the histology were characteristics of cones in rd16/Nrl-/- mice. They appeared at 2 weeks of age and reached the peak at 1 month. However, these cones underwent degeneration, as evidenced by retinal hyperpigmentation since 1.5 months of age followed by vascular attenuation. ERG recordings showed progressively decreasing responses (25% at 2 months and 15% at 3 months), compared with those at 1 month. When the transplantation was done at P14, donor rod cells (as marked by GFP expression) 2 weeks later showed morphological changes, including outer segment development (or neurite outgrowth) and integration. The donor cells survived at 2 months after transplantation. ERG recordings showed improvement of the scotopic a-wave amplitude.
Retinal cell replacement may be helpful for preserving the retinal function. Meticulous procedures are mandatory for a successful transplantation. The rd16/Nrl-/- mouse retina can serve as a model for understanding the preservation of cones in foveal region of patients with CEP290 (or other) mutations and for optimizing the protocols for cell-based therapy.
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