Intraperitoneal chromophore injections delay early-onset and rapid retinal cone degeneration in a mouse model of Leber congenital amaurosis

Dai, Xufeng; Jin, Xumin; Ye, Qian; Huang, Haixiao; Lan, Duo; Lu, Chunjie; Bao, Jinhua; Chen, Hao

doi:10.1016/j.exer.2021.108776

Cited by 3 publications

(1 citation statement)

References 57 publications

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“…For RPE65 mutation-associated LCA, alternative therapeutic approaches are available, including exogenous supplementation of 11-cis-retinaldehyde (11cRAL) which serves as the chromophore for retinal photopigments. However, exogenous 11cRAL supplementation only recovered short-term retinal function, exhibiting no discernible benefits 10 days post the final treatment ( 36 ). In 2017, a significant milestone was reached with the FDA’s approval of a gene-based drug for commercial use.…”

Section: Discussionmentioning

confidence: 99%

Unlocking therapeutic potential: dual gene therapy for ameliorating the disease phenotypes in a mouse model of RPE65 Leber congenital amaurosis

Liu,

Tai,

et al. 2024

Front. Med.

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Leber congenital amaurosis (LCA) is the most common genetic cause of congenital visual impairment in infants and children. Patients with LCA who harbor RPE65 mutations exhibit a deficiency in photoreceptor rhodopsin, leading to severe night blindness and visual impairment following birth. Since either gene replacement therapy or anti-apoptosis therapy alone cannot maintain both functional and morphological normality for a long time in the animal model, we propose a robust treatment strategy, that is, gene replacement therapy combined with anti-apoptotic therapy to protect photoreceptors from further degeneration while compensating for lost RPE65 function. Here, rd12 mice were injected subretinally at postnatal day 14 with four vector administrations, respectively. At 6 months after treatment, it was discovered that injection of three vectors, AAV8 (Y733F)-CBA-hRPE65, AAV8(Y733F)-CBA-hRPE65-BCL-2-L10 and mixture of half-dose AAV8(Y733F)-CBA-hRPE65 and half-dose AAV8 (Y733F)-CBA-BCL-2-L10, could partially restore the visual function of rd12 mice. Meanwhile, these treated eyes also exhibited a thicker outer nuclear layer (ONL) structure. However, despite the fact that the eyes of rd12 mice injected with the AAV8 (Y733F)-CBA-BCL-2-L10 vector displayed a slightly thicker ONL structure compared to untreated eyes, the visual function of the treated eyes did not recover. Continuing the observation period to 12 months after treatment, we found that compared to rd12 mice at 6-month post-treatment, rd12 mice injected with AAV8 (Y733F)-CBA-hRPE65 or mixture of half-dose AAV8(Y733F)-CBA-hRPE65 and half-dose AAV8 (Y733F)-CBA-BCL-2-L10 exhibited varying degrees of decline in both visual function and ONL thickness. However, in the case of rd12 mice injected with the AAV8(Y733F)-CBA-hRPE65-BCL-2-L10 vector, the ONL thickness remains consistent at both 6 and 12 months after treatment. These mice continued to maintain a relatively strong visual function and showed restoration in the levels of RPE65 and Rhodopsin protein expression. Our findings illustrate that early postnatal treatment with AAV vectors containing both the hRPE65 gene and the Bcl-2L10 anti-apoptotic gene provide enhanced and sustained retinal protection.

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Section: Discussionmentioning

confidence: 99%

Unlocking therapeutic potential: dual gene therapy for ameliorating the disease phenotypes in a mouse model of RPE65 Leber congenital amaurosis

Liu,

Tai,

et al. 2024

Front. Med.

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Morphological characterization of retinal development from birth to adulthood via retinal thickness assessment in mice: a systematic review

Brais-Brunet,

Boudoux,

Dehaes

2025

Experimental Eye Research

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Leukemia Inhibitory Factor Protects against Degeneration of Cone Photoreceptors Caused by RPE65 Deficiency

Dong,

Zhen,

Zou

et al. 2024

CMC

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Background:: Retinal pigment epithelium (RPE) 65 is a key enzyme in the visual cycle involved in the regeneration of 11-cis-retinal. Mutations in the human RPE65 gene cause Leber’s congenital amaurosis (LCA), a severe form of an inherited retinal disorder. Animal models carrying Rpe65 mutations develop early-onset retinal degeneration. In particular, the cones degenerate faster than the rods. To date, gene therapy has been used successfully to treat RPE65-associated retinal disorders. However, gene therapy does not completely prevent progressive retinal degeneration in patients, possibly due to the vulnerability of cones in these patients. In the present study, we tested whether leukemia inhibitory factor (LIF), a trophic factor, protects cones in rd12 mice harboring a nonsense mutation in Rpe65. Methods:: LIF was administrated to rd12 mice by intravitreal microinjection. Apoptosis of retinal cells was analyzed by TUNEL assay. The degeneration of cone cells was evaluated by immunostaining of retinal sections and retinal flat-mounts. Signaling proteins regulated by LIF in the retinal and cultured cells were determined by immunoblotting. Results:: Intravitreal administration of LIF activated the STAT3 signaling pathway, thereby inhibiting photoreceptor apoptosis and preserving cones in rd12 mice. Niclosamide (NCL), an inhibitor of STAT3 signaling, effectively blocked STAT3 signaling and autophagy in cultured 661W cells treated with LIF. Co-administration of LIF with NCL to rd12 mice abolished the protective effect of LIF, suggesting that STAT3 signaling and autophagy mediate the protection. Conclusion:: IF is a potent factor that protects cones in rd12 mice. This finding implies that LIF can be used in combination with gene therapy to achieve better therapeutic outcomes for patients with RPE65-associated LCA.

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Intraperitoneal chromophore injections delay early-onset and rapid retinal cone degeneration in a mouse model of Leber congenital amaurosis

Cited by 3 publications

References 57 publications

Unlocking therapeutic potential: dual gene therapy for ameliorating the disease phenotypes in a mouse model of RPE65 Leber congenital amaurosis

Unlocking therapeutic potential: dual gene therapy for ameliorating the disease phenotypes in a mouse model of RPE65 Leber congenital amaurosis

Morphological characterization of retinal development from birth to adulthood via retinal thickness assessment in mice: a systematic review

Leukemia Inhibitory Factor Protects against Degeneration of Cone Photoreceptors Caused by RPE65 Deficiency

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