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Background <p>Retinitis pigmentosa (RP) is a leading cause of blindness affecting 2 million people worldwide. Mutations in cyclic nucleotide-gated channel alpha 1 (<i>CNGA1</i>) account for 2–8% of autosomal recessive RP with no available treatment. Here we further evaluate our previously developed <i>Cnga1</i><sup><i>-/-</i></sup> mouse model. We aim to present detailed phenotype data and assess the therapeutic efficacy of gene augmentation in this model.</p> Methods <p>The retinal function and structure of <i>Cnga1</i><sup>-/-</sup> mice were accessed from postnatal month 1 to 6. AAV8-<i>hRHO</i>-<i>mCnga1</i> was constructed and delivered into the subretinal space of 2-week-old <i>Cnga1</i><sup>-/-</sup> mice. Retinal function, photoreceptor survival, and vision-guided behavior were evaluated following treatment.</p> Results <p>Here we show that <i>Cnga1</i><sup>-/-</sup> mice have a similar phenotype to human patients, characterized by an early loss of rod-mediated retinal function and progressive photoreceptor degeneration, which is nearly complete by 6 months of age. Gene augmentation therapy results in robust expression of correctly localized CNGA1 protein, sustained rescue of retinal function and long-term preservation of photoreceptors for at least 9 months. Treated mice also show improved performance in a vision-guided behavior test. RNA-seq reveals upregulation of genes associated with phototransduction.</p> Conclusions <p>To the best of our knowledge, this work demonstrates for the first time that a gene augmentation approach can restore vision and preserves photoreceptors in an animal model of <i>CNGA1</i>-RP. These findings pave the way for future development of gene augmentation therapy for patients with <i>CNGA1</i>-RP.</p>

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Gene augmentation therapy restores vision and preserves photoreceptors in a mouse model of CNGA1-retinitis pigmentosa

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月2日

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  • Yidong Wu,
  • Tianyuan Zhao,
  • Yazhi Wang,
  • Ting Zhang,
  • Chenyue Hang,
  • Yafang Wang,
  • Yang Liu,
  • Zhixuan Chen,
  • Jieqiong Chen,
  • Tong Li,
  • Junran Sun,
  • Huixun Jia,
  • Lei Zhang,
  • Fenghua Wang,
  • Xiaoling Wan,
  • Xiaodong Sun

摘要

Background

Retinitis pigmentosa (RP) is a leading cause of blindness affecting 2 million people worldwide. Mutations in cyclic nucleotide-gated channel alpha 1 (CNGA1) account for 2–8% of autosomal recessive RP with no available treatment. Here we further evaluate our previously developed Cnga1-/- mouse model. We aim to present detailed phenotype data and assess the therapeutic efficacy of gene augmentation in this model.

Methods

The retinal function and structure of Cnga1-/- mice were accessed from postnatal month 1 to 6. AAV8-hRHO-mCnga1 was constructed and delivered into the subretinal space of 2-week-old Cnga1-/- mice. Retinal function, photoreceptor survival, and vision-guided behavior were evaluated following treatment.

Results

Here we show that Cnga1-/- mice have a similar phenotype to human patients, characterized by an early loss of rod-mediated retinal function and progressive photoreceptor degeneration, which is nearly complete by 6 months of age. Gene augmentation therapy results in robust expression of correctly localized CNGA1 protein, sustained rescue of retinal function and long-term preservation of photoreceptors for at least 9 months. Treated mice also show improved performance in a vision-guided behavior test. RNA-seq reveals upregulation of genes associated with phototransduction.

Conclusions

To the best of our knowledge, this work demonstrates for the first time that a gene augmentation approach can restore vision and preserves photoreceptors in an animal model of CNGA1-RP. These findings pave the way for future development of gene augmentation therapy for patients with CNGA1-RP.