Liver-directed AAV gene therapy normalizes disease symptoms and provides cross-correction in a model of lysosomal acid lipase deficiency.

IF 12.1 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-28 DOI:10.1016/j.ymthe.2024.10.022
Patricia Lam, Deborah A Zygmunt, Anna Ashbrook, Cong Yan, Hong Du, Paul T Martin
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Abstract

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.

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肝脏定向 AAV 基因疗法可使溶酶体酸性脂肪酶缺乏症小鼠模型的疾病症状正常化并提供交叉校正。
溶酶体酸性脂肪酶缺乏症(LAL-D)是由 LIPA 基因突变引起的,该基因编码的溶酶体酶可将甘油三酯和胆固醇酯水解为游离脂肪酸和游离胆固醇。本研究的目的是利用腺相关病毒(AAV)开发一种治疗 LAL-D 的单一疗法。在早期(1-2天)和晚期(8周)使用rscAAVrh74.LP1.LIPA(一种肝脏定向AAV基因疗法)进行治疗,可使Lipa-/-小鼠在24周龄时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。rscAAVrh74.LP1.LIPA治疗可使所有测试组织(包括肝脏、脾脏、肠道、肌肉和大脑)的LAL酶活性升高至高于野生型水平,而且治疗引起的转基因蛋白血清抗体反应极小。在小鼠 8 周大时用 1x1013 vg/kg 的 AAV 处理可显著延长其存活时间,所有 AAV 处理过的小鼠的存活时间都超过了未处理过的 Lipa-/- 小鼠的最大存活时间。这些结果表明,这种肝脏定向 LIPA 基因疗法有可能成为治疗 LAL-D 的一种变革性疗法。
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来源期刊
Molecular Therapy
Molecular Therapy 医学-生物工程与应用微生物
CiteScore
19.20
自引率
3.20%
发文量
357
审稿时长
3 months
期刊介绍: Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.
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