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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy
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Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy

机译：在rAAV1-AAT基因治疗的临床试验中，尽管存在T淋巴细胞反应，但转基因表达仍保持稳定

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摘要

Alpha-1 antitrypsin (AAT) deficiency is well-suited as a target for human gene transfer. We performed a phase 1, open-label, dose-escalation clinical trial of a recombinant adeno-associated virus (rAAV) vector expressing normal (M) AAT packaged into serotype 1 AAV capsids delivered by i.m. injection. Nine AAT-deficient subjects were enrolled sequentially in cohorts of 3 each at doses of 6.9 × 10~(12), 2.2 × 10~(13), and 6.0 × 10~(13) vector genome particles per patient. Four subjects receiving AAT protein augmentation discontinued therapy 28 or 56 days before vector administration. Vector administration was well tolerated, with only mild local reactions and 1 unrelated serious adverse event (bacterial epididymitis). There were no changes in hematology or clinical chemistry parameters. M-specific AAT was expressed above background in all subjects in cohorts 2 and 3 and was sustained at levels 0.1 % of normal for at least 1 year in the highest dosage level cohort, despite development of neutralizing antibody and IFN-γ enzyme-linked immunospot responses to AAV1 capsid at day 14 in all subjects. These findings suggest that immune responses to AAV capsid that develop after i.m. injection of a serotype 1 rAAV vector expressing AAT do not completely eliminate transduced cells in this context.
机译：Alpha-1抗胰蛋白酶（AAT）缺陷非常适合作为人类基因转移的靶标。我们进行了重组腺相关病毒（rAAV）载体的1期，开放标签，剂量递增的临床试验，该载体表达包装在i.m递送的血清型1 AAV衣壳中的正常（M）AAT。注射。 9名AAT缺陷受试者按患者每人6.9×10〜（12），2.2×10〜（13）和6.0×10〜（13）个载体基因组颗粒的剂量依次入组3个队列。在给予载体之前28或56天，接受AAT蛋白增强的四名受试者中止治疗。媒介给药的耐受性良好，仅有轻度的局部反应和1个无关的严重不良事件（细菌附睾炎）。血液学或临床化学参数没有变化。尽管中和抗体和IFN-γ酶联免疫斑点的发展，M特异性AAT在第2和第3组的所有受试者中均高于背景，并且在最高剂量组中维持正常水平的0.1％至少一年。第14天所有受试者对AAV1衣壳的反应。这些发现表明，在A.m.后，对AAV衣壳的免疫反应发生了。在这种情况下，注射表达AAT的血清型1 rAAV载体并不能完全消除转导的细胞。

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    Mark L. Brantly; Jeffrey D. Chulay; Lili Wang; Christian Mueller; Margaret Humphries; L. Terry Spencer; Farshid Rouhani; Thomas J. Conlon; Roberto Calcedo; Michael R. Betts; Carolyn Spencer; Barry J. Byrne; James M. Wilson; Terence R. Flotte;

  • 作者单位

    Department of Medicine, University of Florida, Gainesville, FL 32611;

    Applied Genetic Technologies Corporation, Alachua, FL 32615;

    Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104;

    Department of Pediatrics and Gene Therapy Center, University of Massachusetts, Worcester, MA 01655;

    Department of Pediatrics and Gene Therapy Center, University of Massachusetts, Worcester, MA 01655;

    Boston Children's Hospital, Boston, MA 02115;

    Department of Medicine, University of Florida, Gainesville, FL 32611;

    Powell Gene Therapy Center, University of Florida, Gainesville, FL 32610;

    Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104;

    Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104;

    Boston Children's Hospital, Boston, MA 02115;

    Powell Gene Therapy Center, University of Florida, Gainesville, FL 32610;

    Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104;

    Department of Pediatrics and Gene Therapy Center, University of Massachusetts, Worcester, MA 01655;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    AAV; CTL; immune response; pulmonary; gene therapy;

    机译：AAV;CTL;免疫反应;肺基因治疗;

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