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Treating Bietti crystalline dystrophy in a high-fat diet-exacerbated murine model using gene therapy


Lipid metabolic deficiencies are associated with many genetic disorders. Bietti crystalline dystrophy (BCD), a blindness-causing inherited disorder with changed lipid profiles, is more common in Chinese and Japanese than other populations. Our results reveal that mouse models lacking Cyp4v3 have less physiological and functional changes than those of BCD patients with this gene defect. After the administration of a high-fat diet (HFD), the occurrence of retinal lesions were both accelerated and aggregated in the Cyp4v3−/− mouse models, implying that changed lipid levels were not only associated factors but also risk factors to BCD patients. Facilitated by the results, we found that the reduced electroretinography waveforms and retinal thickness observed in the HFD-induced mouse models were effectively recovered after subretinal delivery of a human CYP4V2 gene carried by an adeno-associated virus vector, which demonstrates the potential curability of BCD by gene therapy.

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Fig. 1: Derivation and long-term evaluation of Cyp4v3−/− mice.
Fig. 2: High-fat diet accelerates and aggravates the retinal lesions of Cyp4v3−/− mice.
Fig. 3: Electroretinography (ERG) changes in Cyp4v3−/− mice fed high-fat diet.
Fig. 4: Gene therapy strategy and retina observation.
Fig. 5: Evaluation of electroretinograms (ERGs) and retinal thickness after AAV injection.
Fig. 6: Evaluation of RPE free fatty acid profile.


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We thank Shi-Wen Li, Xi-Li Zhu for their help with confocal laser scanning microscope.


This work was supported by the National Key Research and Development Program (2019YFA0110800 to WL, 2017YFA0103803 to QZ); the Key Research Program of the Chinese Academy of Sciences (KJZD-SW-L03); the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16030403 to WL); the National Natural Science Foundation of China (31621004 to QZ and WL); the Key Research Projects of the Frontier Science of the Chinese Academy of Sciences (QYZDY-SSW-SMC002 to QZ, QYZDB-SSW-SMC022 to WL); the National Postdoctoral Program for Innovative Talents (BX201600161 to ZL); the Beijing Natural Science Foundation (7184236 to XZ);the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2018PT32029 to R.S.); the Chinese Ministry of Science and Technology (2010DFB33430).

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WL, RS, and QZ conceived the project and designed the experiments; BQ, SW, GJ, ZL, XZ, and LG performed the experiments; BQ and ZL analyzed the data; WL, YZ, and BQ wrote the manuscript with the assistance of the other authors.

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Correspondence to Ruifang Sui or Wei Li.

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Qu, B., Wu, S., Jiao, G. et al. Treating Bietti crystalline dystrophy in a high-fat diet-exacerbated murine model using gene therapy. Gene Ther 27, 370–382 (2020).

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