Immune Responses to Intramuscular Administration of Alipogene Tiparvovec (AAV1-LPLS447X) in a Phase II Clinical Trial of Lipoprotein Lipase Deficiency Gene Therapy
Immune Responses to Intramuscular Administration of Alipogene Tiparvovec (AAV1-LPLS447X) in a Phase II Clinical Trial of Lipoprotein Lipase Deficiency Gene Therapy
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DOI：
10.1089/hum.2013.169
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发表时间：
2014-03-01
影响因子：
4.2
通讯作者：
Gaudet, Daniel
中科院分区：
文献类型：
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作者：
Ferreira, Valerie;Twisk, Jaap;Gaudet, Daniel
用于基因治疗的腺相关病毒（AAV）载体的细胞免疫应答与转基因表达减弱和疗效丧失有关。研究了这种细胞免疫应答对脂源提帕沃韦克（Glybera; AAV1- lpls447x; unite）临床疗效的影响。脂源提帕沃韦克是一种基因疗法，由肌肉注射重组AAV1介导脂蛋白脂肪酶（LPL）的肌肉定向表达组成。5例LPL缺乏症（LPLD）患者肌肉注射1 × 10(12) gc/kg脂原替帕沃韦。所有受试者在给药前不久开始免疫抑制治疗，并持续到给药后12周。在5例LPLD患者中，研究了针对AAV1和LPLS447X的全身抗体和T细胞反应，以及注射肌肉中的局部细胞免疫反应。尽管对AAV1衣壳蛋白有短暂的全身细胞反应和稳定的体液免疫反应，但仍证明了长期的转基因表达。五名受试者中有四名发现细胞浸润，但与不良临床事件或炎症标志物升高无关。与此一致的是，浸润中的CD8+ T细胞缺乏细胞毒性。此外，浸润中还发现了FoxP3+/CD4+ T细胞，提示局部耐受有多种机制。肌内注射脂原替帕沃韦诱导的全身和局部免疫反应似乎对安全性没有影响，也没有阻止LPL转基因表达。这些发现支持在LPLD患者中使用脂肪基因替帕沃韦，并表明基于肌肉定向的aav基因治疗仍然是治疗人类疾病的一种有希望的方法。
Cellular immune responses to adeno-associated viral (AAV) vectors used for gene therapy have been linked to attenuated transgene expression and loss of efficacy. The impact of such cellular immune responses on the clinical efficacy of alipogene tiparvovec (Glybera; AAV1-LPLS447X; uniQure), a gene therapy consisting of intramuscular administration of a recombinant AAV1 mediating muscle-directed expression of lipoprotein lipase (LPL), was investigated. Five subjects with LPL deficiency (LPLD) were administered intramuscularly with a dose of 1x10(12) gc/kg alipogene tiparvovec. All subjects were treated with immune suppression starting shortly before administration of alipogene tiparvovec and maintained until 12 weeks after administration. Systemic antibody and T cell responses against AAV1 and LPLS447X, as well as local cellular immune responses in the injected muscle, were investigated in five LPLD subjects. Long-term transgene expression was demonstrated despite a transient systemic cellular response and a stable humoral immune response against the AAV1 capsid protein. Cellular infiltrates were found in four of the five subjects but were not associated with adverse clinical events or elevation of inflammation markers. Consistent herewith, CD8+ T cells in the infiltrates lacked cytotoxic potential. Furthermore, FoxP3+/CD4+ T cells were found in the infiltrates, suggesting that multiple mechanisms contribute to local tolerance. Systemic and local immune responses induced by intramuscular injection of alipogene tiparvovec did not appear to have an impact on safety and did not prevent LPL transgene expression. These findings support the use of alipogene tiparvovec in individuals with LPLD and indicate that muscle-directed AAV-based gene therapy remains a promising approach for the treatment of human diseases.