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Review
. 2014 Jan;25(1):3-11.
doi: 10.1089/hum.2013.2527.

Adenovirus: the first effective in vivo gene delivery vector

Ronald G Crystal  1
Affiliations
Review

Adenovirus: the first effective in vivo gene delivery vector

Ronald G Crystal. Hum Gene Ther. 2014 Jan.
No abstract available

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Figures

<b>FIG. 1.</b>
FIG. 1.
Schematic of a typical adenovirus gene transfer vector genome. In an adenovirus vector, the early (E) genes in the E1 region are deleted (to prevent replication) as is the E3 region (to make more room for the expression cassette). The inverted terminal repeats (ITR), packaging signal (ψ), and the late (L) genes remain in the vector. The deletions allow for an expression cassette of up to 7–8 kb. A typical expression cassette, including a promoter, the transgene, and stop/polyA sequences, is inserted into the deleted El region. The construct is typically packaged in 293 cells, a cell line that expresses the human adenovirus E1 region, thus providing the components necessary for replication. The vector enters cells through the fiber interacting with the coxsackie-adenovirus (CAR) receptor and secondary integrin (e.g., αVβ3–5) receptors.
<b>FIG. 2.</b>
FIG. 2.
The first example of effective in vivo gene transfer using an adenovirus vector. Top: Examples from a notebook in 1991 from the Crystal laboratory, Pulmonary Branch, the National Heart, Lung, and Blood Institute, of a lung of a cotton rat that had received intratracheal E1−E3− adenovirus coding for β-galactosidase under control of an RSV promoter 7 days earlier. Shown is a control and with AdRSVβgal vector. There is extensive β-galactosidase expression throughout the lung. Bottom: The publication in Science was the first article describing effective in vivo gene transfer with a recombinant replication-deficient adenovirus (Rosenfeld et al., 1991).
<b>FIG. 3.</b>
FIG. 3.
The publication in Cell demonstrating effective in vivo transfer of the human cystic fibrosis transmembrane conductance regulator (CFTR) cDNA to the epithelium of cotton rats. The expression of the human CFTR protein in the airway epithelium was detected by an antibody 2 weeks after intratracheal administration of an E1−E3− serotype adenovirus vector expressing the human CFTR cDNA (Rosenfeld et al., 1992).
<b>FIG. 4.</b>
FIG. 4.
The first human gene therapy with a recombinant virus. On April 16, 1993, at the Clinical Center, NIH, a 23-year-old man with cystic fibrosis received an adenovirus coding for the normal human CFTR cDNA to the nasal epithelium. On the next day, the patient underwent fiberoptic bronchoscopy and 2×108 plaque-forming units of the vector was delivered through a catheter to the bronchial epithelium. The airways can be seen on the monitor. In the photo, left to right: staff nurse delivering the vector via a syringe, G. McElvaney, R. Crystal, staff nurse, and J. Hay. Successful gene transfer to the airway epithelium was demonstrated by antihuman CFTR antibody detection of CFTR before (left) and 4 days after (right) vector administration. The CFTR protein is stained red (Rosenfeld et al., 1992).
<b>FIG. 5.</b>
FIG. 5.
Quantitative assessment of the airway epithelium for the percentage of exogenous CFTR mRNA derived from the adenovirus vector compared with endogenous CFTR mRNA (individual's own CFTR gene expression) as a function of dose and time (baseline, days 3 and 30) after endobronchial spray of the first administration (cycle 1), second administration (cycle 2), and third administration (cycle 3) of the vector. The dashed line represents the target 5% level of exogenous vector-derived CFTR mRNA, that is, the level above which there should be sufficient levels of normal CFTR mRNA to correct the defect. Each symbol represents a different individual. Note that correction was achieved 3 days after the first administration (vector-derived mRNA levels all above the 5% level needed for correction), but this wanes by 30 days. Repeat administration (cycle 2) barely achieved this level, and the third administration resulted in no vector-derived CFTR mRNA expression. Adapted from Harvey et al. (1999).
<b>FIG. 6.</b>
FIG. 6.
The first human trial of inducing cardiac angiogenesis with an adenovirus gene transfer vector. In 1997, we initiated a clinical trial to treat individuals with diffuse coronary artery disease with direct cardiac administration of an adenovirus coding for vascular endothelial growth factor (VEGF) 121 (Rosengart et al., 1999a,b, 2013). Clockwise, left to right: T. Rosengart, R. Crystal, and K. Krieger.
<b>FIG. 7.</b>
FIG. 7.
Induction of hair growth in a C57Bl/6 mouse 2 weeks after administration of an adenovirus vector coding for sonic hedgehog. To visualize hair growth, the hair of the mouse was bleached with blond hair dye to provide contrast for assessing new growth of the natural black hair of the mouse. The tuft of black hair is apparent (Sato et al., 1999).
See this image and copyright information in PMC

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