Lentiviral Gene Therapy for Mucopolysaccharidosis II with Tagged Iduronate 2-Sulfatase Prevents Life-Threatening Pathology in Peripheral Tissues But Fails to Correct Cartilage.

IF 3.9 3区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Human gene therapy Pub Date : 2024-04-01 Epub Date: 2024-02-02 DOI:10.1089/hum.2023.177
Fabio Catalano, Eva C Vlaar, Zina Dammou, Drosos Katsavelis, Tessa F Huizer, Giacomo Zundo, Marianne Hoogeveen-Westerveld, Esmeralda Oussoren, Hannerieke J M P van den Hout, Gerben Schaaf, Karin Pike-Overzet, Frank J T Staal, Ans T van der Ploeg, W W M Pim Pijnappel
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Abstract

Deficiency of iduronate 2-sulfatase (IDS) causes Mucopolysaccharidosis type II (MPS II), a lysosomal storage disorder characterized by systemic accumulation of glycosaminoglycans (GAGs), leading to a devastating cognitive decline and life-threatening respiratory and cardiac complications. We previously found that hematopoietic stem and progenitor cell-mediated lentiviral gene therapy (HSPC-LVGT) employing tagged IDS with insulin-like growth factor 2 (IGF2) or ApoE2, but not receptor-associated protein minimal peptide (RAP12x2), efficiently prevented brain pathology in a murine model of MPS II. In this study, we report on the effects of HSPC-LVGT on peripheral pathology and we analyzed IDS biodistribution. We found that HSPC-LVGT with all vectors completely corrected GAG accumulation and lysosomal pathology in liver, spleen, kidney, tracheal mucosa, and heart valves. Full correction of tunica media of the great heart vessels was achieved only with IDS.IGF2co gene therapy, while the other vectors provided near complete (IDS.ApoE2co) or no (IDSco and IDS.RAP12x2co) correction. In contrast, tracheal, epiphyseal, and articular cartilage remained largely uncorrected by all vectors tested. These efficacies were closely matched by IDS protein levels following HSPC-LVGT. Our results demonstrate the capability of HSPC-LVGT to correct pathology in tissues of high clinical relevance, including those of the heart and respiratory system, while challenges remain for the correction of cartilage pathology.

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使用标记 IDS 的慢病毒基因疗法治疗粘多糖病 II,可防止外周组织出现危及生命的病变,但无法矫正软骨。
伊度酸2-硫酸酯酶(IDS)缺乏会导致II型粘多糖病,这是一种溶酶体贮积症,其特点是糖胺聚糖(GAGs)的全身性蓄积,会导致破坏性的认知能力下降以及危及生命的呼吸系统和心脏并发症。我们以前曾发现,造血干细胞和祖细胞介导的慢病毒基因疗法(HSPC-LVGT)采用带有 IGF2 或 ApoE2(而非 RAP12x2)的标记 IDS,能有效预防 MPS II 小鼠模型的脑部病变。在此,我们报告了 HSPC-LVGT 对外周病理学的影响,并分析了 IDS 的生物分布。我们发现,所有载体的 HSPC-LVGT 都能完全纠正肝脏、脾脏、肾脏、气管粘膜和心脏瓣膜中的 GAG 累积和溶酶体病理学。只有 IDS.IGF2co 基因疗法能完全纠正心脏大血管的中膜,而其他载体则几乎完全(IDS.ApoE2co)或没有(IDSco 和 IDS.RAP12x2co)纠正。与此相反,气管、骺软骨和关节软骨在所有测试载体的作用下基本未得到校正。这些效果与 HSPC-LVGT 后的 IDS 蛋白水平密切相关。我们的研究结果表明,HSPC-LVGT 有能力纠正与临床高度相关的组织病理,包括心脏和呼吸系统,但在纠正软骨病理方面仍存在挑战。
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来源期刊
Human gene therapy
Human gene therapy 医学-生物工程与应用微生物
CiteScore
6.50
自引率
4.80%
发文量
131
审稿时长
4-8 weeks
期刊介绍: Human Gene Therapy is the premier, multidisciplinary journal covering all aspects of gene therapy. The Journal publishes in-depth coverage of DNA, RNA, and cell therapies by delivering the latest breakthroughs in research and technologies. Human Gene Therapy provides a central forum for scientific and clinical information, including ethical, legal, regulatory, social, and commercial issues, which enables the advancement and progress of therapeutic procedures leading to improved patient outcomes, and ultimately, to curing diseases.
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