共 45 条
Recombinant adeno-associated virus serotype 4 mediates unique and exclusive long-term transduction of retinal pigmented epithelium in rat, dog, and nonhuman primate after subretinal delivery
被引:147
作者:

Weber, M
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机构: CHU Hotel DIEU, Lab Therapie Geni, INSERM, F-44035 Nantes 01, France

Rabinowitz, J
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机构: CHU Hotel DIEU, Lab Therapie Geni, INSERM, F-44035 Nantes 01, France

Provost, N
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机构: CHU Hotel DIEU, Lab Therapie Geni, INSERM, F-44035 Nantes 01, France

Conrath, H
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机构: CHU Hotel DIEU, Lab Therapie Geni, INSERM, F-44035 Nantes 01, France

Folliot, S
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机构: CHU Hotel DIEU, Lab Therapie Geni, INSERM, F-44035 Nantes 01, France

Briot, D
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机构: CHU Hotel DIEU, Lab Therapie Geni, INSERM, F-44035 Nantes 01, France

Chérel, Y
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机构: CHU Hotel DIEU, Lab Therapie Geni, INSERM, F-44035 Nantes 01, France

Chenuaud, P
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机构: CHU Hotel DIEU, Lab Therapie Geni, INSERM, F-44035 Nantes 01, France

Samulski, J
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机构: CHU Hotel DIEU, Lab Therapie Geni, INSERM, F-44035 Nantes 01, France

Moullier, P
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机构: CHU Hotel DIEU, Lab Therapie Geni, INSERM, F-44035 Nantes 01, France

Rolling, F
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机构: CHU Hotel DIEU, Lab Therapie Geni, INSERM, F-44035 Nantes 01, France
机构:
[1] CHU Hotel DIEU, Lab Therapie Geni, INSERM, F-44035 Nantes 01, France
[2] CHU Hotel DIEU, Serv Ophthalmol, F-44000 Nantes, France
[3] Univ N Carolina, Gene Therapy Ctr, Chapel Hill, NC 27599 USA
[4] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA
[5] Ecole Natl Vet, Anat Pathol Lab, INRA, UR 703, F-44000 Nantes, France
关键词:
AAV vectors;
serotypes;
retina;
gene transfer;
tropism;
GFP;
rat;
dog;
primate;
D O I:
10.1016/S1525-0016(03)00098-4
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:
previously described chimeric recombinant adeno-associated virus (rAAV) vectors 2/4 and 2/5 as the most efficient vectors in rat retina. We now characterize these two vectors carrying the CMV.gfp genome following subretinal injection in the Wistar rat, beagle dog, and cynomolgus macaque. Both serotypes displayed stable GFP expression for the duration of the experiment (6 months) in all three animal models. Similar to the AAV-2 serotype, AAV-2/5 transduced both RPE and photoreceptor cells, with higher level of transduction in photoreceptors, whereas rAAV-2/4 transduction was unambiguously restricted to RPE cells. This unique specificity found conserved among all three species makes AAV-2/4-derived vectors attractive for retinal diseases originating in RPE such as Leber congenital amaurosis (RPE65) or retinitis pigmentosa due to a mutated mertk gene. To provide further important preclinical data, vector shedding was monitored by PCR in various biological fluids for 2 months post-rAAV administration. Following rAAV-2/4 and -5 subretinal delivery in dogs (n = 6) and in nonhuman primates (n = 2), vector genome was found in lacrymal and nasal fluids for up to 3-4 days and in the serum for up to 15-20 days. Overall, these findings will have a practical impact on the development of future gene therapy trials of retinal diseases.
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页码:774 / 781
页数:8
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