Strategy to detect pre-existing immunity to AAV gene therapy.
Strategy to detect pre-existing immunity to AAV gene therapy.
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DOI：
10.1038/gt.2017.95
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发表时间：
2017-12
期刊：
影响因子：
5.1
通讯作者：
Fong S
中科院分区：
文献类型：
--
作者：
Falese L;Sandza K;Yates B;Triffault S;Gangar S;Long B;Tsuruda L;Carter B;Vettermann C;Zoog SJ;Fong S
基因治疗可能提供一种新的治疗选择，特别是对严重血友病患者，根据最近的研究。然而，对腺相关病毒（AAV）具有预先存在的免疫力的个体可能不太可能从基于AAV载体的治疗中获益。为了研究人类中预先存在的AAV5免疫性，我们验证了两种互补的、灵敏的和可扩展的体外测定以检测AAV5总抗体和转导抑制（TI）。使用这两种测定法，我们发现来自100名健康男性个体的53%的样品在两种测定法中均为阴性，18%在两种测定法中均为阳性，5%为总抗体阳性但TI阴性，并且有趣的是，24%为总抗体阴性但TI活性阳性，表明人血浆中存在基于非抗体的中和因子。从血友病A患者的24份样本中获得了类似的结果。在这些结果的基础上，我们描述了一种双重检测策略的发展，以确定没有总AAV5抗体或中和因子的个体，这些个体可能更有可能对AAV5定向基因治疗产生反应。这些检测方法提供了一个通用的、可跨实验室转移的平台，以评估大量患者群体中AAV5抗体和中和因子的全球流行率，从而帮助制定临床开发策略。
Gene therapy may offer a new treatment option, particularly for patients with severe hemophilia, based on recent research. However, individuals with pre-existing immunity to adeno-associated viruses (AAVs) may be less likely to benefit from AAV vector-based therapies. To study pre-existing AAV5 immunity in humans, we validated two complementary, sensitive, and scalable in vitro assays to detect AAV5 total antibodies and transduction inhibition (TI). Using these two assays, we found that 53% of samples from 100 healthy male individuals were negative in both assays, 18% were positive in both assays, 5% were positive for total antibodies but negative for TI and, of interest, 24% were negative for total antibodies but positive for TI activity, suggesting the presence of non-antibody-based neutralizing factors in human plasma. Similar findings were obtained with 24 samples from individuals with hemophilia A. On the basis of these results, we describe the development of a dual-assay strategy to identify individuals without total AAV5 antibodies or neutralizing factors who may be more likely to respond to AAV5-directed gene therapy. These assays offer a universal, transferrable platform across laboratories to assess the global prevalence of AAV5 antibodies and neutralizing factors in large patient populations to help inform clinical development strategies.
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影响因子：
--
作者：
Calcedo, Roberto;Morizono, Hiroki;Wilson, James M.
通讯作者：
Wilson, James M.
影响因子：
82.9
作者：
Mingozzi, Federico;Maus, Marcela V.;High, Katherine A.
通讯作者：
High, Katherine A.
影响因子：
6
作者：
Jaski, Brian E.;Jessup, Mariell L.;Mancini, Donna M.;Cappola, Thomas P.;Pauly, Daniel F.;Greenberg, Barry;Borow, Kenneth;Dittrich, Howard;Zsebo, Krisztina M.;Hajjar, Roger J.
通讯作者：
Hajjar, Roger J.
影响因子：
5.1
作者：
Li, C.;Narkbunnam, N.;Monahan, P. E.
通讯作者：
Monahan, P. E.
影响因子：
37.8
作者：
Jessup M;Greenberg B;Mancini D;Cappola T;Pauly DF;Jaski B;Yaroshinsky A;Zsebo KM;Dittrich H;Hajjar RJ;Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) Investigators
通讯作者：
Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) Investigators