Lysosomal acid lipase deficiency (LAL-D) is caused by mutations in the LIPA gene, which encodes the lysosomal enzyme that hydrolyzes triglycerides and cholesteryl esters to free fatty acids and free cholesterol. The objective of this study was to develop a curative single-treatment therapy for LAL-D using adeno-associated virus (AAV). Treatment at both early (1–2 days) and late (8-week) timepoints with rscAAVrh74.LP1.LIPA, a liver-directed AAV gene therapy, normalized many disease measures in Lipa−/− mice when measured at 24 weeks of age, including hepatosplenomegaly, serum transaminase activity, organ triglyceride and cholesterol levels, and biomarkers of liver inflammation and fibrosis. For most measures, liver-directed therapy was superior to therapy utilizing a constitutive tissue expression approach. rscAAVrh74.LP1.LIPA treatment elevated LAL enzyme activity above wild-type levels in all tissues tested, including liver, spleen, intestine, muscle, and brain, and treatment elicited minimal serum antibody responses to transgenic protein. AAV treatment at 8 weeks of age with 1 × 1013 vg/kg extended survival significantly, with all AAV-treated mice surviving beyond the maximal lifespan of untreated Lipa−/− mice. These results show that this liver-directed LIPA gene therapy has the potential to be a transformative treatment for LAL-D.

中文翻译：

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肝脏靶向 AAV 基因治疗可使疾病症状正常化，并在溶酶体酸性脂肪酶缺乏症模型中提供交叉校正


溶酶体酸脂肪酶缺乏症 （LAL-D） 是由 LIPA 基因突变引起的，该基因编码将甘油三酯和胆固醇酯水解为游离脂肪酸和游离胆固醇的溶酶体酶。本研究的目的是使用腺相关病毒 （AAV） 开发一种治疗性 LAL-D 的单一治疗疗法。rscAAVrh74.LP1.LIPA（一种肝脏定向的 AAV 基因疗法）在早期（1-2 天）和晚期（8 周）时间点进行治疗，在 24 周龄时测量时，Lipa-/-小鼠的许多疾病指标恢复正常，包括肝脾肿大、血清转氨酶活性、器官甘油三酯和胆固醇水平，以及肝脏炎症和纤维化的生物标志物。对于大多数测量，肝脏定向治疗优于使用组成型组织表达方法的治疗。rscAAVrh74.LP1.LIPA 处理使所有测试组织（包括肝脏、脾脏、肠道、肌肉和大脑）的 LAL 酶活性升高到野生型水平以上，并且处理对转基因蛋白的血清抗体反应最小。在 8 周龄时以 1 × 1013 vg/kg 的 AAV 治疗显着延长了存活率，所有 AAV 处理的小鼠存活率超过了未经治疗的 Lipa - / - 小鼠的最大寿命。这些结果表明，这种肝脏定向的 LIPA 基因疗法有可能成为 LAL-D 的变革性治疗方法。