Virus-mediated transduction of murine retina with adeno-associated virus: Effects of viral capsid and genome size

被引:160
作者
Yang, GS
Schmidt, M
Yan, ZY
Lindbloom, JD
Harding, TC
Donahue, BA
Engelhardt, JF
Kotin, R
Davidson, BL
机构
[1] Univ Iowa, Coll Med, Dept Internal Med, Program Gene Therapy, Iowa City, IA 52242 USA
[2] Univ Iowa, Coll Med, Dept Otolaryngol, Program Gene Therapy, Iowa City, IA 52242 USA
[3] Univ Iowa, Coll Med, Dept Neurol, Program Gene Therapy, Iowa City, IA 52242 USA
[4] Univ Iowa, Coll Med, Dept Physiol & Biophys, Program Gene Therapy, Iowa City, IA 52242 USA
[5] Univ Iowa, Coll Med, Dept Anat & Cell Biol, Program Gene Therapy, Iowa City, IA 52242 USA
[6] NHLBI, Bethesda, MD 20892 USA
[7] Cell Genesys Inc, Foster City, CA USA
关键词
D O I
10.1128/JVI.76.15.7651-7660.2002
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Gene therapy vectors based on adeno-associated viruses (AAVs) show promise for the treatment of retinal degenerative diseases. In prior work, subretinal injections of AAV2, AAV5, and AAV2 pseudotyped with AAV5 capsids (AAV2/5) showed variable retinal pigmented epithelium (RPE) and photoreceptor cell transduction, while AAV2/1 predominantly transduced the RPE. To more thoroughly compare the efficiencies of gene transfer of AAV2, AAV3, AAV5, and AAV6, we quantified, using stereological methods, the kinetics and efficiency of AAV transduction to mouse photoreceptor cells. We observed persistent photoreceptor and RPE transduction by AAV5 and AAV2 up to 31 weeks and found that AAV5 transduced a greater volume than AAV2. AAV5 containing full-length or half-length genomes and AAV2/5 transduced comparable numbers of photoreceptor cells with similar rates of onset of expression. Compared to AAV2, AAV5 transduced significantly greater numbers of photoreceptor cells at 5 and 15 weeks after surgery (greater than 1,000 times and up to 400 times more, respectively). Also, there were 30 times more genome copies in eyes injected with AAV2/5 than in eyes injected with AAV2. Comparing AAVs with half-length genomes, AAV5 transduced only four times more photoreceptor cells than AAV2 at 5 weeks and nearly equivalent numbers at 15 weeks. The enhancement of transduction was seen at the DNA level, with 50 times more viral genome copies in retinas injected with AAV having short genomes than in retinas injected with AAV containing full-length ones. Subretinal injection of AAV2/6 showed only RPE transduction at 5 and 15 weeks, while AAV2/3 did not transduce retinal cells. We conclude that varying genome length and AAV capsids may allow for improved expression and/or gene transfer to specific cell types in the retina.
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页码:7651 / 7660
页数:10
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共 39 条
[21]  
Jeon CJ, 1998, J NEUROSCI, V18, P8936
[22]   Neuron-specific transduction in the rat septohippocampal or nigrostriatal pathway by recombinant adeno-associated virus vectors [J].
Klein, RL ;
Meyer, EM ;
Peel, AL ;
Zolotukhin, S ;
Meyers, C ;
Muzyczka, N ;
King, MA .
EXPERIMENTAL NEUROLOGY, 1998, 150 (02) :183-194
[23]   CLONING OF INFECTIOUS ADENO-ASSOCIATED VIRUS GENOMES IN BACTERIAL PLASMIDS [J].
LAUGHLIN, CA ;
TRATSCHIN, JD ;
COON, H ;
CARTER, BJ .
GENE, 1983, 23 (01) :65-73
[24]   Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal dominant retinitis pigmentosa [J].
Lewin, AS ;
Drenser, KA ;
Hauswirth, WW ;
Nishikawa, S ;
Yasumura, D ;
Flannery, JG ;
LaVail, MM .
NATURE MEDICINE, 1998, 4 (08) :967-971
[25]   Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis [J].
McCarty, DM ;
Monahan, PE ;
Samulski, RJ .
GENE THERAPY, 2001, 8 (16) :1248-1254
[26]   Stable and efficient gene transfer into the retina using an HIV-based lentiviral vector [J].
Miyoshi, H ;
Takahashi, M ;
Gage, FH ;
Verma, IM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (19) :10319-10323
[27]   Normal retina releases a diffusible factor stimulating cone survival in the retinal degeneration mouse [J].
Mohand-Said, S ;
Deudon-Combe, A ;
Hicks, D ;
Simonutti, M ;
Forster, V ;
Fintz, AC ;
Leveillard, T ;
Dreyfus, H ;
Sahel, JA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (14) :8357-8362
[28]   Human fibroblast growth factor receptor 1 is a co-receptor for infection by adeno-associated virus 2 [J].
Qing, K ;
Mah, C ;
Hansen, J ;
Zhou, SZ ;
Dwarki, V ;
Srivastava, A .
NATURE MEDICINE, 1999, 5 (01) :71-77
[29]   Infectious clones and vectors derived from adeno-associated virus (AAV) serotypes other than AAV type 2 [J].
Rutledge, EA ;
Halbert, CL ;
Russell, DW .
JOURNAL OF VIROLOGY, 1998, 72 (01) :309-319
[30]   HELPER-FREE STOCKS OF RECOMBINANT ADENO-ASSOCIATED VIRUSES - NORMAL INTEGRATION DOES NOT REQUIRE VIRAL GENE-EXPRESSION [J].
SAMULSKI, RJ ;
CHANG, LS ;
SHENK, T .
JOURNAL OF VIROLOGY, 1989, 63 (09) :3822-3828