Adenovirus-Associated Defective Virus Particles

Atchison, Robert W.; Casto, Bruce C.; Hammon, William McD.

doi:10.1126/science.149.3685.754

Cited by 803 publications

(464 citation statements)

References 8 publications

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“…[3][4][5][6][7][8][9][10][11][12][13][14] On the basis of the success of some of these animal studies, clinical trials with AAV vectors have recently been initiated in humans with genetically linked ophthalmic diseases. 15,16 Human AAV serotype 2 was originally found as a contaminant in adenovirus preparations 17 and has not been associated with any human pathogenicity. Since then, several other AAV serotypes have been identified with slight variations in amino-acid capsid identity.…”

Section: Introductionmentioning

confidence: 99%

Cellular tropism and transduction properties of seven adeno-associated viral vector serotypes in adult retina after intravitreal injection

et al. 2008

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Recombinant adeno-associated virus (rAAV) vectors are increasingly being used as tools for gene therapy, and clinical trials have begun in patients with genetically linked retinal disorders. Intravitreal injection is optimal for the transduction of retinal ganglion cells (RGCs), although complete selectivity has not been achieved. There may also be advantages in using intravitreal approaches for the transduction of photoreceptors. Here we compared the cellular tropism and transduction efficiency of rAAV2/1, -2/2, -2/3, -2/4, -2/5, -2/6 and -2/8 in adult rat retina after intravitreal injection. Each vector encoded green fluorescent protein (GFP), and the number, laminar distribution and morphology of transduced GFP + cells were determined using fluorescent microscopy. Assessment of transduced cell phenotype was based on cell morphology and immunohistochemistry. rAAV2/2 and rAAV2/6 transduced the greatest number of cells, whereas rAAV2/5 and rAAV2/8 were least efficient. Most vectors primarily transduced RGCs; however, rAAV2/6 had a more diverse tropism profile, with 46% identified as amacrine or bipolar cells, 23% as RGCs and 22% as Mü ller cells. Mü ller cells were also frequently transduced by rAAV2/4. The highest photoreceptor transduction was seen after intravitreal rAAV2/3 injection. These data facilitate the design and selection of rAAV vectors to target specific retinal cells, potentially leading to an improved gene therapy for various human retinal pathologies.

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Section: Introductionmentioning

confidence: 99%

Cellular tropism and transduction properties of seven adeno-associated viral vector serotypes in adult retina after intravitreal injection

et al. 2008

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“…First, wild-type AAV is a defective, nonpathogenic parvovirus which requires coinfection with adenovirus or herpes virus for replication. [5][6][7] In contrast to retroviruses, these viruses can efficiently infect both dividing and nondividing cells. 8 Second, the vector system for generating rAAV is simple; the AAV terminal repeats are the only cis elements which are necessary and sufficient for replication, packaging and possibly integration.…”

Section: Introductionmentioning

confidence: 99%

Adeno-associated virus-mediated delivery of erythropoietin leads to sustained elevation of hematocrit in nonhuman primates

Zhou¹,

Je²,

Escobedo³

et al. 1998

Gene Ther

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Recombinant adeno-associated virus encoding the monhematocrits reached 62 and 75% by week 10 (from prekey erythropoietin gene (rAAV-cm-Epo) was generated injection values of 38 and 40%, respectively) and remained and tested for its potential to confer long-term expression elevated throughout the study period (28 weeks). Circulatof the gene product following intramuscular injection. A ing Epo levels were also elevated throughout the study persingle intramuscular injection of 2 × 10 12 rAAV-cm-Epo pariod. Our data demonstrate the potential for long-term gene ticles into two baboons led to sustained high circulating expression in large animals by a single intramuscular injecEpo levels and a concomitant increase in hematocrit. The tion of a recombinant adeno-associated virus (rAAV) vector.

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“…10 The adenoviral gene products, whether supplied by infection or plasmid transfection, are needed to create a favorable intracellular milieu for efficient AAV replication and propagation. [11][12][13][14] Unfortunately, the generation of replication-competent wild-type-like AAV by non-homologous recombination has recently been shown to occur in this transfection system. 15,16 In addition, cotransfection (or tri-transfection) methods are inherently inefficient due to the requirement for three separate 'hits' on any given cell.…”

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confidence: 99%

Production of recombinant adeno-associated virus vectors using a packaging cell line and a hybrid recombinant adenovirus

1999

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Recombinant adeno-associated virus (rAAV) vectors are tious rAAV when the vector genome is transfected into the under consideration for a wide variety of gene therapy cell line as plasmid DNA. We have now extended this applications. One of the limitations of the rAAV vector sysapproach by constructing a hybrid recombinant adenovirus tem has been the difficulty in producing the vector in suf-(rAd) that contains a complete rAAV vector genome in the ficient quantity for adequate preclinical and clinical evalu-E1 region. This hybrid virus is used to deliver the rAAV ation. A common method for vector production involves genome to the packaging cell line (in the place of plasmid large-scale transient transfection of multiple plasmids into transfection). rAAV is produced when the packaging cell cultured cells. Because this approach might not be feasible line is infected with the hybrid adenovirus and wild-type for clinical scale manufacturing, we have sought adenovirus. This method avoids the need for plasmid approaches for rAAV vector production that avoid transient transfection and is adaptable to large-scale manufacturtransfection procedures. In previously reported work, we ing processes. generated an AAV packaging cell line that produces infecKeywords: adeno-associated virus vector; adenovirus; packaging cell line Recombinant adeno-associated viruses (rAAV) have shown significant potential as a gene transfer vector for the treatment of a variety of inherited and acquired diseases. This excitement has been fueled in part by the demonstration that rAAV efficiently transduces many mouse and primate tissues and organs in vivo. Long-term transgene expression has now been observed in the liver, lung, CNS, retina and cardiac and skeletal muscle. [1][2][3][4][5][6][7][8][9] A significant limitation of rAAV vectors has been the cumbersome and technically challenging methods required for the generation of high-titer vector preparations. In many laboratories, rAAV is routinely produced using a two-plasmid transient transfection system. One plasmid contains an expression cassette for the gene of interest that is flanked by the AAV ITRs; the second plasmid encodes for AAV helper functions (rep and cap genes). rAAV is produced by co-transfection of both plasmids into an appropriate cell line (usually 293 cells) concurrent with wild-type adenovirus infection. A recent variation of this strategy calls for a third plasmid to be transfected that expresses several adenovirus early gene products (E1B, E2A, E4, VA1 RNA); this improvement apparently eliminates the need for wild-type adenovirus Correspondence: PR Johnson,

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Adenovirus-Associated Defective Virus Particles

Cited by 803 publications

References 8 publications

Cellular tropism and transduction properties of seven adeno-associated viral vector serotypes in adult retina after intravitreal injection

Cellular tropism and transduction properties of seven adeno-associated viral vector serotypes in adult retina after intravitreal injection

Adeno-associated virus-mediated delivery of erythropoietin leads to sustained elevation of hematocrit in nonhuman primates

Production of recombinant adeno-associated virus vectors using a packaging cell line and a hybrid recombinant adenovirus

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