Striatal delivery of rAAV-hAADC to rats with preexisting immunity to AAV

被引：76

作者：

Sanftner, LM ^{[1
]}

Suzuki, BM ^{[1
]}

Doroudchi, MM ^{[1
]}

Feng, L ^{[1
]}

McClelland, A ^{[1
]}

Forsayeth, JR ^{[1
]}

Cunningham, J ^{[1
]}

机构：

[1] Avigen Inc, Alameda, CA 94502 USA

来源：

MOLECULAR THERAPY | 2004年 / 9卷 / 03期

关键词：

adeno-associated virus; aromatic L-amino acid decarboxylase; Parkinson disease; brain; neutralizing antibody response; AAV-hAADC;

D O I：

10.1016/j.ymthe.2003.12.005

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

We tested the hypotheses that initial immunization of rats with rAAV might limit subsequent transduction by rAAV-hAADC when sterecitaxically infused into the striatum and that the level of inhibition would correlate with AAV neutralizing antibody titers. Immunohistochemical detection of AADC and analysis by stereology revealed that the control group (no immunization) had the greatest volume of distribution of AADC (20.32 +/- 2.03 mm(3)) (+/-SD). There was a 58% decrease in spread (8.46 +/- 3.67 mm(3), P < 0.008) in the high-dose immunization group (5 x 10(10) vg rAAV-null). Transduction weakly correlated with preexisting titer levels of neutralizing antibody at the time of intrastriatal rAAV-hAADC infusion. Only rats with neutralizing antibody titers of 1: 1208 332 had significantly decreased AADC transgene expression compared to the unimmunized control group. Immunohistochemistry on serial sections for inflammatory markers including CFAP, CD11b, CD4, and CD8a revealed normal morphology and no cellular infiltration, suggesting little immune reaction in the CNS. We conclude that rAAV vectors can transduce brain tissue in the context of preexisting immunity, but that efficiency of transduction declines significantly in the presence of very high titers of neutralizing antibodies. These results have important implications for gene therapy for CNS disorders.

引用

页码：403 / 409

页数：7

共 32 条

[1] Additional transduction events after subretinal readministration of recombinant adeno-associated virus [J].