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<p>Neuronal intranuclear inclusion disease (NIID) is an adult-onset neurodegenerative disease caused by expanded GGC repeats in the 5’ untranslated region of the human-specific <i>NOTCH2NLC</i> gene. The high sequence similarity between <i>NOTCH2NLC</i> and its paralogs poses a significant challenge for precise gene editing. Here, we develop a CRISPR/spCas9-based gene-editing strategy that precisely excises the expanded GGC repeats in <i>NOTCH2NLC</i> without detectable off-target effects on the highly homologous <i>NOTCH2/NOTCH2NL</i> family genes (&lt;2% sequence divergence at this locus). The efficacy, specificity and safety of this approach are rigorously validated across multiple experimental models, including human cell lines, NIID iPSCs, and our previously established transgenic NIID mouse model. Our results demonstrate that precise excision of the expanded GGC repeats effectively alleviates NIID-related neuropathological, molecular and behavioral abnormalities. This study establishes the proof of concept for genome editing as a therapeutic strategy for NIID and other related repeat expansion disorders.</p>

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Precise excision of expanded GGC repeats in NOTCH2NLC via CRISPR/Cas9 for treating neuronal intranuclear inclusion disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月13日

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  • Nina Xie,
  • Yongcheng Pan,
  • Huichun Tong,
  • Yingqi Lin,
  • Ying Jiang,
  • Zhiqin Wang,
  • Juan Wan,
  • Wendiao Zhang,
  • Xinhui Wang,
  • Xiaobo Sun,
  • Sen Yan,
  • Peng Yin,
  • Qiying Sun,
  • Chengzhi Qi,
  • Yun Tian,
  • Lu Shen,
  • Hong Jiang,
  • Desheng Liang,
  • Beisha Tang,
  • Shihua Li,
  • Xiao-Jiang Li,
  • Qiong Liu

摘要

Neuronal intranuclear inclusion disease (NIID) is an adult-onset neurodegenerative disease caused by expanded GGC repeats in the 5’ untranslated region of the human-specific NOTCH2NLC gene. The high sequence similarity between NOTCH2NLC and its paralogs poses a significant challenge for precise gene editing. Here, we develop a CRISPR/spCas9-based gene-editing strategy that precisely excises the expanded GGC repeats in NOTCH2NLC without detectable off-target effects on the highly homologous NOTCH2/NOTCH2NL family genes (<2% sequence divergence at this locus). The efficacy, specificity and safety of this approach are rigorously validated across multiple experimental models, including human cell lines, NIID iPSCs, and our previously established transgenic NIID mouse model. Our results demonstrate that precise excision of the expanded GGC repeats effectively alleviates NIID-related neuropathological, molecular and behavioral abnormalities. This study establishes the proof of concept for genome editing as a therapeutic strategy for NIID and other related repeat expansion disorders.