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

  • Authors: Dong S.1, Zhen F.2, Zou T.3, Zhou Y.4, Wu J.5, Wang T.6, Zhang H.6
  • Affiliations:
    1. Department of Ophthalmology,, The First Affiliated Hospital of Zhengzhou University, Henan Provincial Ophthalmic Hospital,
    2. Department of Ophthalmology,, The First Affiliated Hospital of Zhengzhou University, Henan Provincial Ophthalmic Hospital
    3. The Key Laboratory for Human Disease Gene Study of Sichuan Province, Center for Medical Genetics,, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China
    4. Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Henan Provincial Ophthalmic Hospital,
    5. Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Henan Provincial Ophthalmic Hospital,
    6. The Key Laboratory for Human Disease Gene Study of Sichuan Province, Center for Medical Genetics, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China
  • Issue: Vol 31, No 25 (2024)
  • Pages: 4022-4033
  • Section: Anti-Infectives and Infectious Diseases
  • URL: https://cijournal.ru/0929-8673/article/view/644914
  • DOI: https://doi.org/10.2174/0109298673240896231027053716
  • ID: 644914

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Full Text

Abstract

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 administered 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::LIF 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.

About the authors

Shuqian Dong

Department of Ophthalmology,, The First Affiliated Hospital of Zhengzhou University, Henan Provincial Ophthalmic Hospital,

Email: info@benthamscience.net

Fangyuan Zhen

Department of Ophthalmology,, The First Affiliated Hospital of Zhengzhou University, Henan Provincial Ophthalmic Hospital

Email: info@benthamscience.net

Tongdan Zou

The Key Laboratory for Human Disease Gene Study of Sichuan Province, Center for Medical Genetics,, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China

Email: info@benthamscience.net

Yongwei Zhou

Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Henan Provincial Ophthalmic Hospital,

Email: info@benthamscience.net

Jiahui Wu

Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Henan Provincial Ophthalmic Hospital,

Email: info@benthamscience.net

Ting Wang

The Key Laboratory for Human Disease Gene Study of Sichuan Province, Center for Medical Genetics, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China

Email: info@benthamscience.net

Houbin Zhang

The Key Laboratory for Human Disease Gene Study of Sichuan Province, Center for Medical Genetics, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China

Author for correspondence.
Email: info@benthamscience.net

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