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<p>Pathogenic variants in <i>ATP6V1B2</i>, which encodes a critical subunit of vacuolar-type H+-ATPases (V-ATPases), disrupt lysosomal acidification via haploinsufficiency and clinically manifest as intellectual disability and seizure disorders. Despite significant morbidity, mechanism-based therapies remain an unmet need. Through integrated clinical analysis of a Chinese cohort and systematic literature review, we delineated genotype-phenotype correlations in <i>ATP6V1B2</i>-related syndromes. Isogenic HEK293T models (<i>ATP6V1B2</i><sup>R506X/+</sup> and <i>ATP6V1B2</i><sup>R506X/R506X</sup>) were generated using CRISPR/Cas9 for dynamic lysosomal pH monitoring via ratiometric RpH-LAMP1-3×flag imaging to evaluate pathophysiological mechanisms. Parallel investigations in <i>Atp6v1b2</i><sup>R506X/R506X</sup> mice incorporated continuous video-EEG monitoring, behavioral assessments, western blot analyses, and transmission electron microscopy to evaluate therapeutic responses. Drug concentrations in plasma and brain homogenates were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Clinical analysis revealed central nervous system manifestations (epilepsy, intellectual disability, developmental delay) as primary morbidity determinants. Cellular studies demonstrated significant increase of lysosomal pH in mutant cells compared to wild-type control. Remarkably, treatment with the cAMP analog CPT-cAMP restored lysosomal acidification in a concentration-dependent manner. In vivo studies confirmed spontaneous seizure activity in mutant mice and CPT-cAMP’s penetration of the BBB was confirmed by LC-MS/MS. Intraperitoneal CPT-cAMP administration (20 mg/kg) exerted triple therapeutic effects: (1) significant reduction in seizure frequency, (2) improved cognitive performance in behavioral paradigms, and (3) restoration of autophagic flux through resolution of autophagosome accumulation. These findings establish proof-of-concept for cAMP-mediated lysosomal pH modulation as a viable therapeutic strategy. Our results position CPT-cAMP as a promising candidate for addressing both neurological and cognitive manifestations in <i>ATP6V1B2</i>-related disorders.</p><p></p>

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Therapeutic potential of cAMP-mediated lysosomal pH modulation in ATP6V1B2-related neuropathology

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月27日

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  • Lu Zheng,
  • Weihao Zhao,
  • Guang Yang,
  • Shiwei Qiu,
  • Yahong Li,
  • Lin Gao,
  • Gege Wei,
  • Ying Ma,
  • Jiangping Xie,
  • Xue Gao,
  • Linyan Chen,
  • Xiaoge Li,
  • Rongfeng Lin,
  • Wei Xiong,
  • Yongyi Yuan,
  • Pu Dai

摘要

Pathogenic variants in ATP6V1B2, which encodes a critical subunit of vacuolar-type H+-ATPases (V-ATPases), disrupt lysosomal acidification via haploinsufficiency and clinically manifest as intellectual disability and seizure disorders. Despite significant morbidity, mechanism-based therapies remain an unmet need. Through integrated clinical analysis of a Chinese cohort and systematic literature review, we delineated genotype-phenotype correlations in ATP6V1B2-related syndromes. Isogenic HEK293T models (ATP6V1B2R506X/+ and ATP6V1B2R506X/R506X) were generated using CRISPR/Cas9 for dynamic lysosomal pH monitoring via ratiometric RpH-LAMP1-3×flag imaging to evaluate pathophysiological mechanisms. Parallel investigations in Atp6v1b2R506X/R506X mice incorporated continuous video-EEG monitoring, behavioral assessments, western blot analyses, and transmission electron microscopy to evaluate therapeutic responses. Drug concentrations in plasma and brain homogenates were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Clinical analysis revealed central nervous system manifestations (epilepsy, intellectual disability, developmental delay) as primary morbidity determinants. Cellular studies demonstrated significant increase of lysosomal pH in mutant cells compared to wild-type control. Remarkably, treatment with the cAMP analog CPT-cAMP restored lysosomal acidification in a concentration-dependent manner. In vivo studies confirmed spontaneous seizure activity in mutant mice and CPT-cAMP’s penetration of the BBB was confirmed by LC-MS/MS. Intraperitoneal CPT-cAMP administration (20 mg/kg) exerted triple therapeutic effects: (1) significant reduction in seizure frequency, (2) improved cognitive performance in behavioral paradigms, and (3) restoration of autophagic flux through resolution of autophagosome accumulation. These findings establish proof-of-concept for cAMP-mediated lysosomal pH modulation as a viable therapeutic strategy. Our results position CPT-cAMP as a promising candidate for addressing both neurological and cognitive manifestations in ATP6V1B2-related disorders.