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<p>Aniridia is a rare congenital vision-loss disorder that is caused primarily by heterozygous loss-of-function variants in the <i>PAX6</i> gene. There is currently no curative treatment. Gene therapy has emerged as a powerful strategy for treating inherited retinal diseases. Here, we aim to establish a systemic <i>PAX6</i> gene-augmentation therapy capable of addressing retinal pathologic phenotypes in a preclinical <i>Sey</i> mouse model of aniridia. We evaluated the intravenous delivery of FLAG-tagged <i>PAX6</i> packaged in the AAV-PHP.eB capsid. Treatment was administered on postnatal day 21 to mimic the average age at diagnosis and the likely early therapeutic window in humans. The transcript levels of the virally-delivered PAX6 were 7.1% at 1 month, and 8.9% at 5 months, of Wt endogenous levels. These transcripts produced PAX6 protein in the ganglion (GCL) and inner nuclear cell layers. Importantly, in this pilot study, a significant increase in GCL thickness at 5 months post-injection was also observed. Furthermore, this structural change in the <i>Sey</i> retina was preceded by a significant increase in <i>Notch1</i> transcription at 1-month post-injection. Thus, we demonstrated the first successful viral-mediated augmentation of <i>PAX6</i> in the retina in a preclinical mouse model of aniridia, resulting in a phenotypic change at the structural and molecular levels.</p>

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First pilot study of intravenous rAAV-PAX6 gene therapy increases retinal-ganglion-cell-layer thickness and Notch1 transcription in a mouse model of aniridia

  • 期刊论文

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  • 发表日期：

    2026年3月9日

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  • Diana Djaksigulova,
  • Sif G. Kaad,
  • Andrea J. Korecki,
  • Siu Ling Lam,
  • Tess C. Lengyell,
  • Elizabeth M. Simpson

摘要

Aniridia is a rare congenital vision-loss disorder that is caused primarily by heterozygous loss-of-function variants in the PAX6 gene. There is currently no curative treatment. Gene therapy has emerged as a powerful strategy for treating inherited retinal diseases. Here, we aim to establish a systemic PAX6 gene-augmentation therapy capable of addressing retinal pathologic phenotypes in a preclinical Sey mouse model of aniridia. We evaluated the intravenous delivery of FLAG-tagged PAX6 packaged in the AAV-PHP.eB capsid. Treatment was administered on postnatal day 21 to mimic the average age at diagnosis and the likely early therapeutic window in humans. The transcript levels of the virally-delivered PAX6 were 7.1% at 1 month, and 8.9% at 5 months, of Wt endogenous levels. These transcripts produced PAX6 protein in the ganglion (GCL) and inner nuclear cell layers. Importantly, in this pilot study, a significant increase in GCL thickness at 5 months post-injection was also observed. Furthermore, this structural change in the Sey retina was preceded by a significant increase in Notch1 transcription at 1-month post-injection. Thus, we demonstrated the first successful viral-mediated augmentation of PAX6 in the retina in a preclinical mouse model of aniridia, resulting in a phenotypic change at the structural and molecular levels.