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Background <p>Precise control of transgene expression is essential for safe and effective AAV gene therapies. While capsid engineering has advanced tissue targeting, progress in developing regulatory elements that confine expression to specific tissues has lagged. This gap limits the ability to minimize off-target expression and associated safety risks, emphasizing the need for improved tissue-specific regulatory control.</p> Results <p>Here, we evaluated 12 computationally designed tissue-specific promoters generated by Asimov’s proprietary algorithm. Promoters driving a heat-stable human placental alkaline phosphatase reporter gene were packaged into AAV6·2FF and administered to C57BL/6 mice intranasally, intramuscularly, and intraperitoneally. Expression was assessed macroscopically, microscopically, enzymatically and by vector genome quantification. We identified two strictly skeletal muscle-specific promoters independent of the AAV capsid or route of administration used, and two cardiac-specific promoters when administered intraperitoneally.</p> Conclusions <p>These findings demonstrate that computational promoter design can yield elements with great strength and precision that enable safer and more targeted AAV gene therapies and offer a broadly applicable strategy for tissue-specific expression in treating various monogenic diseases.</p>

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Identification of computationally designed skeletal and cardiac promoters with high specificity across AAV delivery routes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月26日

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  • Nicole Zielinska,
  • Erin L. Howard,
  • Brenna A. Y. Stevens,
  • Melanie M. Goens,
  • Cici Yang,
  • Elena S. B. Campbell,
  • Madison E. Hughes,
  • Yanlong Pei,
  • Dinghai Zheng,
  • D. Benjamin Gordon,
  • Alec A. K. Nielsen,
  • Raja R. Srinivas,
  • Jeff L. Caswell,
  • Luis G. Arroyo,
  • Sarah K. Wootton

摘要

Background

Precise control of transgene expression is essential for safe and effective AAV gene therapies. While capsid engineering has advanced tissue targeting, progress in developing regulatory elements that confine expression to specific tissues has lagged. This gap limits the ability to minimize off-target expression and associated safety risks, emphasizing the need for improved tissue-specific regulatory control.

Results

Here, we evaluated 12 computationally designed tissue-specific promoters generated by Asimov’s proprietary algorithm. Promoters driving a heat-stable human placental alkaline phosphatase reporter gene were packaged into AAV6·2FF and administered to C57BL/6 mice intranasally, intramuscularly, and intraperitoneally. Expression was assessed macroscopically, microscopically, enzymatically and by vector genome quantification. We identified two strictly skeletal muscle-specific promoters independent of the AAV capsid or route of administration used, and two cardiac-specific promoters when administered intraperitoneally.

Conclusions

These findings demonstrate that computational promoter design can yield elements with great strength and precision that enable safer and more targeted AAV gene therapies and offer a broadly applicable strategy for tissue-specific expression in treating various monogenic diseases.