Genethon, 1 bis rue de l'internationale, Evry, France.
INTEGRARE research unit UMR_S951 (INSERM, Université Paris-Saclay, Univ Evry), Evry, France.
Nat Commun. 2024 Sep 11;15(1):7965. doi: 10.1038/s41467-024-52002-4.
Current adeno-associated virus (AAV) gene therapy using nature-derived AAVs is limited by non-optimal tissue targeting. In the treatment of muscular diseases (MD), high doses are often required but can lead to severe adverse effects. Here, we rationally design an AAV capsid that specifically targets skeletal muscle to lower treatment doses. We computationally integrate binding motifs of human integrin alphaV beta6, a skeletal muscle receptor, into a liver-detargeting capsid. Designed AAVs show higher productivity and superior muscle transduction compared to their parent. One variant, LICA1, demonstrates comparable muscle transduction to other myotropic AAVs with reduced liver targeting. LICA1's myotropic properties are observed across species, including non-human primate. Consequently, LICA1, but not AAV9, effectively delivers therapeutic transgenes and improved muscle functionality in two mouse MD models (male mice) at a low dose (5E12 vg/kg). These results underline the potential of our design method for AAV engineering and LICA1 variant for MD gene therapy.
目前，使用天然腺相关病毒（AAV）的基因疗法受到非最佳组织靶向性的限制。在肌肉疾病（MD）的治疗中，通常需要高剂量的药物，但这可能会导致严重的不良反应。在这里，我们合理设计了一种能够特异性靶向骨骼肌的 AAV 衣壳，以降低治疗剂量。我们通过计算将人类整合素 αVβ6 的结合基序（一种骨骼肌受体）整合到肝靶向衣壳中。与亲本相比，设计的 AAV 显示出更高的生产能力和优越的肌肉转导效率。一种变体 LICA1 与其他肌性 AAV 相比，具有更低的肝靶向性，但肌肉转导效率相当。LI CA1 的肌向性特性在包括非人类灵长类动物在内的多个物种中都有观察到。因此，LI CA1（而非 AAV9）能够以低剂量（5E12vg/kg）有效递送达治疗性转基因，并改善两种 MD 小鼠模型（雄性小鼠）的肌肉功能。这些结果强调了我们的 AAV 工程设计方法和 LICA1 变体在 MD 基因治疗中的潜力。
