PEGylated helper-dependent adenoviral vectors: highly efficient vectors with an enhanced safety profile

被引:101
作者
Croyle, MA
Le, HT
Linse, KD
Cerullo, V
Toietta, G
Beaudet, A
Pastore, L
机构
[1] Univ Texas, Coll Pharm, Div Pharmaceut, Austin, TX 78712 USA
[2] Univ Texas, Inst Mol & Cellular Biol, Austin, TX 78712 USA
[3] Univ Naples Federico II, CEINGE Biotecnol Avanzate, Dipartimento Biochim & Biotecnol Med, Naples, Italy
[4] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
关键词
helper-dependent adenoviral vectors; PEGylation; toxicology; readministration; immune response;
D O I
10.1038/sj.gt.3302441
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Transgene expression from helper-dependent adenoviral (HD-Ad) vectors is effective and long lasting, but not permanent. Their use is also limited by the host response against capsid proteins that precludes successful gene expression upon readministration. In this report, we test the hypothesis that PEGylation of HD-Ad reduces its toxicity and promotes transgene expression upon readministration. PEGylation did not compromise transduction efficiency in vitro and in vivo and reduced peak serum IL-6 levels two-fold. IL-12 and TNF-alpha levels were reduced three- and sevenfold, respectively. Thrombocytopenia was not detected in mice treated with the PEGylated vector. Serum transaminases were not significantly elevated in mice treated with either vector. Mice immunized with 1 x 10(11) particles of unmodified HD-Ad expressing human alpha-1 antitrypsin (hA1AT) were rechallenged 28 days later with 8 x 10(10) particles of unmodified or PEG-conjugated vector expressing beta-galactosidase. Trace levels of beta-galactosidase (52.23 +/- 19.2 pg/mg protein) were detected in liver homogenates of mice that received two doses of unmodified HD-Ad. Mice rechallenged with PEGylated HD-Ad produced significant levels of beta-galactosidase (5.1 +/- 0.4 x 10(5) pg/mg protein, P = 0.0001). This suggests that PEGylation of HD-Ad vectors may be appropriate for their safe and efficient use in the clinic.
引用
收藏
页码:579 / 587
页数:9
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