Age-Related Seroprevalence of Antibodies Against AAV-LK03 in a UK Population Cohort.
Age-Related Seroprevalence of Antibodies Against AAV-LK03 in a UK Population Cohort.
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DOI：
10.1089/hum.2018.098
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发表时间：
2019-01
影响因子：
4.2
通讯作者：
Baruteau J
中科院分区：
文献类型：
--
作者：
Perocheau DP;Cunningham S;Lee J;Antinao Diaz J;Waddington SN;Gilmour K;Eaglestone S;Lisowski L;Thrasher AJ;Alexander IE;Gissen P;Baruteau J
重组腺相关病毒（rAV）载体是体内基因治疗的一个有前途的平台。针对AAV衣壳的中和抗体（Nab）的存在降低了细胞转导效率，并且是参与临床试验的常见排除标准。正在产生新的工程化衣壳以改善基因递送至靶细胞并促进临床试验的成功;然而，针对此类衣壳的抗体的流行率在很大程度上仍然未知。因此，我们评估了针对新型合成的嗜肝衣壳AAV-LK 03的抗体的血清阳性率。我们测量了免疫球蛋白（IG）G的血清阳性率（即，在323名英国患者（包括260名儿童）和52只幼年恒河猴的队列中，对AAV-LK 03的中和性和非中和性）抗体和Nab进行了研究。我们还对Nab针对野生型AAV 8和AAV 3B衣壳的血清阳性率进行了比较分析。AAV-LK 03的总体IgG血清阳性率在人样品中为39%。滴度随年龄增长而增加。AAV-LK 03、AAV 3B和AAV 8的Nab流行率分别为23%、35%和18%，所有血清型的最低血清流行率在3至17岁之间。针对AAV-LK 03的Nab的存在从最年轻的队列（出生至6个月）中的36%降低至年龄较大的小学学龄儿童（9-11岁）中的7%，然后在成年后期逐渐增加至54%。血清型之间的交叉反应性> 60%。猕猴中AAV-LK 03、AAV 3B和AAV 8的Nab血清阳性率分别为62%、85%和40%。当计划进行AAV基因治疗临床试验时，了解目标人群的血清阳性率至关重要。在研究的人群中，测试的AAV血清型的AAV血清阳性率较低。然而，AAV血清型之间的高交叉反应性仍然是再次注射的障碍。Nab血清阳性率在前十年的变化需要通过纵向研究来证实。这种可能性表明，儿科患者根据年龄对AAV治疗的反应可能不同。如果儿童晚期是一个理想的年龄窗口，那么在母亲Nab水平高的早期进行干预可能具有挑战性。从试验中排除的Nab阳性儿童可以定期重新筛选，因为这种状态可能会发生变化。
Recombinant adeno-associated virus (rAAV) vectors are a promising platform for in vivo gene therapy. The presence of neutralizing antibodies (Nab) against AAV capsids decreases cell transduction efficiency and is a common exclusion criterion for participation in clinical trials. Novel engineered capsids are being generated to improve gene delivery to the target cells and facilitate success of clinical trials; however, the prevalence of antibodies against such capsids remains largely unknown. We therefore assessed the seroprevalence of antibodies against a novel synthetic liver-tropic capsid AAV-LK03. We measured seroprevalence of immunoglobulin (Ig)G (i.e., neutralizing and nonneutralizing) antibodies and Nab to AAV-LK03 in a cohort of 323 UK patients (including 260 pediatric) and 52 juvenile rhesus macaques. We also performed comparative analysis of seroprevalence of Nab against wild-type AAV8 and AAV3B capsids. Overall IgG seroprevalence for AAV-LK03 was 39% in human samples. The titer increased with age. Prevalence of Nab was 23%, 35%, and 18% for AAV-LK03, AAV3B, and AAV8, respectively, with the lowest seroprevalence between 3 and 17 years of age for all serotypes. Presence of Nab against AAV-LK03 decreased from 36% in the youngest cohort (birth to 6 months) to 7% in older primary school-age children (9–11 years) and then progressively increased to 54% in late adulthood. Cross-reactivity between serotypes was >60%. Nab seroprevalence in macaques was 62%, 85%, and 40% for AAV-LK03, AAV3B, and AAV8, respectively. When planning for AAV gene therapy clinical trials, knowing the seropositivity of the target population is critical. In the population studied, AAV seroprevalence for AAV serotypes tested was low. However, high cross-reactivity between AAV serotypes remains a barrier for re-injection. Shifts in Nab seroprevalence during the first decade need to be confirmed by longitudinal studies. This possibility suggests that pediatric patients could respond differently to AAV therapy according to age. If late childhood is an ideal age window, intervention at an early age when maternal Nab levels are high may be challenging. Nab-positive children excluded from trials could be rescreened for eligibility at regular intervals because this status may change.
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影响因子：
3.7
作者：
Brassier A;Gobin S;Arnoux JB;Valayannopoulos V;Habarou F;Kossorotoff M;Servais A;Barbier V;Dubois S;Touati G;Barouki R;Lesage F;Dupic L;Bonnefont JP;Ottolenghi C;De Lonlay P
通讯作者：
De Lonlay P
影响因子：
20.3
作者：
Jiang, Haiyan;Couto, Linda B.;Pierce, Glenn F.
通讯作者：
Pierce, Glenn F.
影响因子：
4.8
作者：
Ling, Chen;Wang, Yuan;Ling, Chang-Quan
通讯作者：
Ling, Chang-Quan
影响因子：
--
作者：
Calcedo, Roberto;Morizono, Hiroki;Wilson, James M.
通讯作者：
Wilson, James M.
影响因子：
5.1
作者：
Li, C.;Narkbunnam, N.;Monahan, P. E.
通讯作者：
Monahan, P. E.