Differential Prevalence of Antibodies Against Adeno-Associated Virus in Healthy Children and Patients with Mucopolysaccharidosis III: Perspective for AAV-Mediated Gene Therapy
Differential Prevalence of Antibodies Against Adeno-Associated Virus in Healthy Children and Patients with Mucopolysaccharidosis III: Perspective for AAV-Mediated Gene Therapy
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DOI：
10.1089/humc.2017.109
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发表时间：
2017-12-01
影响因子：
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通讯作者：
McCarty, Douglas M.
中科院分区：
文献类型：
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作者：
Fu, Haiyan;Meadows, Aaron S.;McCarty, Douglas M.
重组腺相关病毒载体是一种很有前途的基因治疗工具。然而，许多有用的AAV血清型的预先存在的抗体对基因治疗的翻译构成了一个关键的挑战。作为AAV基因治疗粘多糖病(MPS)III患者的一部分，我们调查了MPS IIIA/IIIB患者和健康儿童AAV1-9和Rh 74的血清阳性率。用酶联免疫吸附试验检测αAAV-Ig G，发现2~7岁MPS III患儿AAV1和AAVRH74的血清阳性率显著高于健康对照组。在MPS III受试者中，除8至19岁的MPS IIIA患者中αAAV8和αAAV9抗体增加外，大多数检测的AAV血清型的血清阳性率似乎在8岁之前达到峰值。相比之下，与2至7岁的儿童相比，在8至15岁的健康儿童中，几乎所有测试的AAV血清型的血清阳性率都显著增加。共同患病率和抗体水平的相关性结果遵循先前建立的基于分歧的阿尔法AAV1-9分支位置。有趣的是，αAAVRH74-Abs阳性的个体与αAAV1-9抗体的共患率最低(22-40%)。然而，所有或几乎所有(77-100%)对任何一种血清类型1-9呈阳性的受试者AAVRH74-Ig G也呈阳性。值得注意的是，大多数(78%)的甲型AAV血清阳性个体在所测试的一到五个AAV血清型中也是抗体阳性的，大多数人的甲型AAV抗体水平较低(1：50-100)，而少数人(22%)对六个或更多的甲型AAV血清型的血清阳性，大多是多种血清型的甲型AAV-Ig G水平较高。一般来说，最高的免疫球蛋白水平是对AAV2、AAV3和AAVRh74的反应。这些数据说明了MPS患者和健康儿童中AAV1-9和RH74复杂的血清阳性率曲线，表明AAV血清阳性率与年龄和疾病状况有潜在的关联。不同AAV血清型抗体的广泛共存加强了现有的αAAV-Abs将AAV基因治疗转化为临床应用的挑战，而与载体血清型无关。
Recombinant adeno-associated virus (AAV) vectors are promising gene therapy tools. However, pre-existing antibodies (Abs) to many useful AAV serotypes pose a critical challenge for the translation of gene therapies. As part of AAV gene therapy program for treating mucopolysaccharidosis (MPS) III patients, the seroprevalence profiles of AAV1-9 and rh74 were investigated in MPS IIIA/IIIB patients and in healthy children. Using enzyme-linked immunosorbent assay for alpha AAV-IgG, significantly higher seroprevalence was observed for AAV1 and AAVrh74 in 2- to 7-year-old MPS III patients than in healthy controls. Seroprevalence for the majority of tested AAV serotypes appears to peak before 8 years of age in MPS III subjects, with the exception of increases in alpha AAV8 and alpha AAV9 Abs in 8- to 19-year-old MPS IIIA patients. In contrast, significant increases in seroprevalence were observed for virtually all tested AAV serotypes in 8- to 15-year-old healthy children compared to 2- to 7-year-olds. Co-prevalence and Ab level correlation results followed the previously established divergence-based clade positions of alpha AAV1-9. Interestingly, the individuals positive for alpha AAVrh74-Abs showed the lowest co-prevalence with Abs for alpha AAV1-9 (22-40%). However, all or nearly all (77-100%) of subjects who were seropositive for any of serotypes 1-9 were also positive for AAVrh74-IgG. Notably, the majority (78%) of alpha AAV seropositive individuals were also Ab-positive for one to five of the tested AAV serotypes, mostly with low levels of alpha AAV-Abs (1:50-100), while a minority (22%) were seropositive for six or more AAV serotypes, mostly with high levels of alpha AAV-IgG for multiple serotypes. In general, the highest IgG levels were reactive to AAV2, AAV3, and AAVrh74. The data illustrate the complex seroprevalence profiles of AAV1-9 and rh74 in MPS patients and healthy children, indicating the potential association of AAV seroprevalence with age and disease conditions. The broad co-prevalence of Abs for different AAV serotypes reinforces the challenge of pre-existing alpha AAV-Abs for translating AAV gene therapy to clinical applications, regardless of the vector serotype.