5 Year Expression and Neutrophil Defect Repair after Gene Therapy in Alpha-1 Antitrypsin Deficiency.
5 Year Expression and Neutrophil Defect Repair after Gene Therapy in Alpha-1 Antitrypsin Deficiency.
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DOI：
10.1016/j.ymthe.2017.03.029
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发表时间：
2017-06-07
期刊：
影响因子：
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通讯作者：
Flotte TR
中科院分区：
文献类型：
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作者：
Mueller C;Gernoux G;Gruntman AM;Borel F;Reeves EP;Calcedo R;Rouhani FN;Yachnis A;Humphries M;Campbell-Thompson M;Messina L;Chulay JD;Trapnell B;Wilson JM;McElvaney NG;Flotte TR
α-1抗胰蛋白酶缺乏症是一种单基因疾病，主要由于中性粒细胞弹性蛋白酶的非拮抗作用而导致肺气肿。我们之前曾报道，在α-1抗胰蛋白酶缺乏症患者肌肉注射重组腺相关病毒血清1型α-1抗胰蛋白酶载体一年后，血浆野生型α-1抗胰蛋白酶浓度达到声称治疗水平的2.5%-3.8%。我们分析了血液和肌肉中α-1抗胰蛋白酶的表达和免疫细胞反应。我们还分析了先前报道的中性粒细胞功能标记物，已知在α-1抗胰蛋白酶缺乏患者中发生改变。在这里，我们报告了在没有任何额外的重组腺相关病毒血清-1α-1抗胰蛋白酶载体注射的情况下，这些患者在1-5年的目标水平的2.0%-2.5%的持续表达。此外，我们观察到与疾病相关的中性粒细胞缺陷的部分纠正，包括中性粒细胞弹性蛋白酶抑制、脱颗粒标志和膜结合的抗中性粒细胞抗体。也有证据表明，对腺相关病毒1型衣壳的T调节细胞反应活跃(类似于1年的数据)和耗尽的细胞毒性T细胞反应。这些发现表明，基于肌肉的α-1抗胰蛋白酶基因替代是耐受性的，稳定水平的M-AAT可能在低于先前预期的浓度下发挥有益的中性粒细胞效应。肌肉注射rAAV1载体的α-1抗胰蛋白酶缺陷患者在单次注射后5年内稳定表达转基因，与抗衣壳Treg应答和CD8细胞耗尽相一致。Mueller等人。也观察到疾病生物标志物的部分纠正，尽管血清水平低于蛋白质替代的目标水平。
Alpha-1 antitrypsin deficiency is a monogenic disorder resulting in emphysema due principally to the unopposed effects of neutrophil elastase. We previously reported achieving plasma wild-type alpha-1 antitrypsin concentrations at 2.5%–3.8% of the purported therapeutic level at 1 year after a single intramuscular administration of recombinant adeno-associated virus serotype 1 alpha-1 antitrypsin vector in alpha-1 antitrypsin deficient patients. We analyzed blood and muscle for alpha-1 antitrypsin expression and immune cell response. We also assayed previously reported markers of neutrophil function known to be altered in alpha-1 antitrypsin deficient patients. Here, we report sustained expression at 2.0%–2.5% of the target level from years 1–5 in these same patients without any additional recombinant adeno-associated virus serotype-1 alpha-1 antitrypsin vector administration. In addition, we observed partial correction of disease-associated neutrophil defects, including neutrophil elastase inhibition, markers of degranulation, and membrane-bound anti-neutrophil antibodies. There was also evidence of an active T regulatory cell response (similar to the 1 year data) and an exhausted cytotoxic T cell response to adeno-associated virus serotype-1 capsid. These findings suggest that muscle-based alpha-1 antitrypsin gene replacement is tolerogenic and that stable levels of M-AAT may exert beneficial neutrophil effects at lower concentrations than previously anticipated. Alpha-1 antitrypsin deficient patients injected intramuscularly with a rAAV1 vector demonstrated 5 years of stable transgene expression after a single dose, coincident with an anti-capsid Treg response and exhaustion of CD8 cells. Mueller et al. also observed partial correction of disease biomarkers despite serum levels below the target level for protein replacement.