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<p>Blue cone monochromacy (BCM) is a severe X-linked blinding disorder caused by mutations in the <i>OPN1LW/OPN1MW</i> locus, resulting in impaired cone function and structural degeneration. We conduct a comparative analysis of AAV gene therapy in <i>Opn1mw</i><sup><i>-/-</i></sup><i>/Opn1sw</i><sup><i>-/-</i></sup> (double knockout, DKO) and <i>Opn1mw</i><sup><i>C198R</i></sup><i>/Opn1sw</i><sup><i>-/-</i></sup> (C198R) BCM mouse models to contrast therapeutic outcomes at different stages. We demonstrate the AAV8<sup>Y733F</sup> capsid achieves superior rescue compared to AAV5. Both DKO and C198R models show comparable therapeutic outcomes, with efficacy consistently decreasing in older mice. Structural analysis reveals both models display rapid degenerative changes in cone outer and inner segments. We observe age-related reductions in transgene expression for both models, potentially resulting from decreased cone transducibility, transgene silencing/downregulation, or disease-related genome expression alterations. Notably, the <i>Pde6c</i> and <i>Cngb3</i> promoters maintain robust activity in degenerating cones. These findings suggest use of an optimized cone promoter can ultimately extend the therapeutic window and treatment longevity in BCM cones.</p>

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Molecular mechanisms limiting the AAV gene therapy treatment window in mouse models of blue cone monochromacy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月24日

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  • Brooke A. Brothers,
  • Emily R. Sechrest,
  • Li Ma,
  • Madyson E. Ashcraft,
  • Tongju Guan,
  • Robert J. Barbera,
  • Lee M. Shaw,
  • Becky Chen,
  • Wolfgang Baehr,
  • Gangqing Hu,
  • Peter Stoilov,
  • Wen-Tao Deng

摘要

Blue cone monochromacy (BCM) is a severe X-linked blinding disorder caused by mutations in the OPN1LW/OPN1MW locus, resulting in impaired cone function and structural degeneration. We conduct a comparative analysis of AAV gene therapy in Opn1mw-/-/Opn1sw-/- (double knockout, DKO) and Opn1mwC198R/Opn1sw-/- (C198R) BCM mouse models to contrast therapeutic outcomes at different stages. We demonstrate the AAV8Y733F capsid achieves superior rescue compared to AAV5. Both DKO and C198R models show comparable therapeutic outcomes, with efficacy consistently decreasing in older mice. Structural analysis reveals both models display rapid degenerative changes in cone outer and inner segments. We observe age-related reductions in transgene expression for both models, potentially resulting from decreased cone transducibility, transgene silencing/downregulation, or disease-related genome expression alterations. Notably, the Pde6c and Cngb3 promoters maintain robust activity in degenerating cones. These findings suggest use of an optimized cone promoter can ultimately extend the therapeutic window and treatment longevity in BCM cones.