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B L Davidson

Publications and source records attributed to B L Davidson.

At least 19 recordsLinked to original sources
PubMed2006

RNAi: a potential therapy for the dominantly inherited nucleotide repeat diseases.

Genetic diseases that are accompanied by central nervous system involvement are often fatal. Among these are the autosomal dominant neurogenetic diseases caused by nucleotide repeat expansion. For example, Huntington's disease (HD) and spinal cerebellar ataxia are caused by expansion of a tract of CAGs encoding glutamine. In HD and the other CAG-repeat expansion diseases, the expansion is in the coding region. Myotonic dystrophy is caused by repeat expansions of CUG or CCTG in noncoding regions, and the mutant RNA is disease causing. Treatments for these disorders are limited to symptomatic intervention. RNA interference (RNAi), which is a method for inhibiting target gene expression, provides a unique tool for therapy by attacking the fundamental problem directly. In this review, we describe briefly several representative disorders and their respective molecular targets, and methods to accomplish therapeutic RNAi. Finally, we summarize studies performed to date.

Animals↗
PubMed2006

Venous thromboembolism and the risk of subsequent symptomatic atherosclerosis.

BACKGROUND: Recently, we reported an association between asymptomatic carotid atherosclerosis and venous thromboembolism (VTE) of unknown origin. We hypothesized that patients with VTE of unknown origin would be at a higher risk of developing symptomatic atherosclerosis than patients with VTE induced by known risk factors. METHODS: To examine this hypothesis, we studied 1,919 consecutive patients followed prospectively after their first VTE episode. The primary outcome was non-fatal and fatal symptomatic atherosclerotic disease in patients with VTE of unknown origin as compared to those with secondary VTE. An independent committee assessed all study outcomes, and adjusted hazard ratios (HR) were calculated using the Cox's proportional hazards model. RESULTS: After a median follow-up of 48 and 51 months, respectively, at least one symptomatic atherosclerotic complication was detected in 160 of the 1,063 patients (15.1%) with VTE of unknown origin, and in 73 of the 856 (8.5%) with secondary VTE. After adjusting for age and other risk factors of atherosclerosis, the HR for symptomatic atherosclerotic complications in patients with VTE of unknown origin compared to those with secondary VTE was 1.6 (95% confidence intervals; CI: 1.2-2.0). When the analysis was restricted to patients without previous symptomatic atherosclerosis, the HR became 1.7 (95% CI: 1.1-2.4). CONCLUSIONS: Patients with VTE of unknown origin have a 60% higher risk of developing symptomatic atherosclerotic disease than do patients with secondary venous thrombosis.

Aged↗
PubMed2005

Adeno-associated virus type 4 (AAV4) targets ependyma and astrocytes in the subventricular zone and RMS.

The subventricular zone (SVZ) is one of the neurogenic niches in the adult mammalian brain. The SVZ is of interest for studies on neurogenesis and stem cell therapy. Here, we report specific transduction of ependyma and/or astrocytes by recombinant adeno-associated virus type 4 (AAV4) viral vectors. AAV4 vectors encoding beta-galactosidase or eGFP were injected into the lateral ventricles of neonatal and adult C57BL/6 mouse brains. In addition, SVZ injections were conducted on adult mice. AAV4 vectors show a characteristic transduction of the ependyma independent of delivery route. However, AAV4 virus injected into the SVZ targeted GFAP positive astrocytes forming the glial tube in the SVZ and rostral migratory stream (RMS). Our results introduce AAV4 as a new tool by which to manipulate glial cells in the RMS.

Animals↗
PubMed2004

Transbronchial administration of adenoviral-mediated interleukin-10 gene to the donor improves function in a pig lung transplant model.

Interleukin-10 (IL-10) gene transfection of donor lungs prior to transplantation is an attractive strategy to reduce ischemia-reperfusion induced lung injury. However, experimental data with gene therapy in large animal models of lung transplantation are generally lacking. We have developed a simple clinically applicable technique for adenoviral-mediated gene delivery of human IL-10 to the lung of large animals that provides homogenous gene expression after 12-24 h of transfection. Using this technique of gene delivery, we have studied the dynamics of adenoviral gene delivery to the lung in the setting of lung transplantation. Although there is a persistent inflammatory response to the adenoviral vector, we achieved significant expression of human IL-10 in lung tissue before lung retrieval to obviate the deleterious impact of the adenoviral vector on the donor lung. The administration of adenoviral-mediated human IL-10 to the donor lung reduced ischemia-reperfusion injury and improved graft function after lung transplantation in this pig lung transplantation model. Transfection of adenoviral-mediated human IL-10 to the donor lung prevented the release of inflammatory cytokines such as IL-6 in lung tissue and plasma. We have demonstrated that IL-10 gene therapy has significant potential to prevent or treat the inflammatory response associated with ischemia-reperfusion injury in lung transplantation. In the future, IL-10 gene therapy could also be used for immunomodulation or tolerance induction.

Adenoviridae↗
PubMed2004

Compliance with recommended prophylaxis for venous thromboembolism: improving the use and rate of uptake of clinical practice guidelines.

Although several authoritative, evidence-based, guidelines for the prevention of venous thromboembolism (VTE) have been published, the use of VTE prophylaxis in routine clinical practice varies markedly. Even in orthopedic surgery, the indication for which prophylaxis is used most often, a significant proportion of surgeons do not use routine prophylaxis. When prophylaxis is used, guideline recommendations are often not followed. A number of factors may contribute to the under-use of guidelines. Physician-related factors include: a lack of awareness of, or familiarity with, the guidelines; a perception that VTE is not a significant problem or that VTE prophylaxis is ineffective; and concern about potential bleeding risks. The guidelines may also be perceived to be too complicated or difficult to apply in a routine manner. In addition, a lack of facilities or resources may also present a barrier to implementation of the guidelines. A number of strategies are being investigated in an attempt to improve compliance with guidelines for VTE prophylaxis. For example, the Investigators Against Thromboembolism (INATE) initiative has developed a simplified pocket guideline on VTE prophylaxis in orthopedic and trauma surgery in order to raise awareness of the current guideline recommendations.

Cooperative Behavior↗
PubMed2003

Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism.

BACKGROUND: The standard initial treatment of hemodynamically stable patients with pulmonary embolism is intravenous unfractionated heparin, requiring laboratory monitoring and hospitalization. METHODS: We conducted a randomized, open-label trial involving 2213 patients with acute symptomatic pulmonary embolism to compare the efficacy and safety of the synthetic antithrombotic agent fondaparinux with those of unfractionated heparin and to document noninferiority in terms of efficacy. Patients received either fondaparinux (5.0, 7.5, or 10.0 mg in patients weighing less than 50, 50 to 100, or more than 100 kg, respectively) subcutaneously once daily or a continuous intravenous infusion of unfractionated heparin (ratio of the activated partial-thromboplastin time to a control value, 1.5 to 2.5), both given for at least five days and until the use of vitamin K antagonists resulted in an international normalized ratio above 2.0. The primary efficacy outcome was the three-month incidence of the composite end point of symptomatic, recurrent pulmonary embolism (nonfatal or fatal) and new or recurrent deep-vein thrombosis. RESULTS: Forty-two of the 1103 patients randomly assigned to receive fondaparinux (3.8 percent) had recurrent thromboembolic events, as compared with 56 of the 1110 patients randomly assigned to receive unfractionated heparin (5.0 percent), for an absolute difference of -1.2 percent in favor of fondaparinux (95 percent confidence interval, -3.0 to 0.5). Major bleeding occurred in 1.3 percent of the patients treated with fondaparinux and 1.1 percent of those treated with unfractionated heparin. Mortality rates at three months were similar in the two groups. Of the patients in the fondaparinux group, 14.5 percent received the drug in part on an outpatient basis. CONCLUSIONS: Once-daily, subcutaneous administration of fondaparinux without monitoring is at least as effective and is as safe as adjusted-dose, intravenous administration of unfractionated heparin in the initial treatment of hemodynamically stable patients with pulmonary embolism.

Aged↗
PubMed2003

Viral-mediated delivery of the late-infantile neuronal ceroid lipofuscinosis gene, TPP-I to the mouse central nervous system.

Classical late-infantile neuronal ceroid lipofuscinosis (LINCL) is caused by mutations in tripeptidyl peptidase I (TPP-I), a pepstatin-insensitive lysosomal protease, resulting in neurodegeneration, acute seizures, visual and motor dysfunction. In vitro studies suggest that TPP-I is secreted from cells and subsequently taken up by neighboring cells, similar to other lysosomal enzymes. As such, TPP-I is an attractive candidate for enzyme replacement or gene therapy. In the present studies, we examined the feasibility of gene transfer into mouse brain using recombinant adenovirus (Ad), feline immunodeficiency virus (FIV) and adeno-associated virus (AAV) vectors expressing TPP-I, after single injections into the striatum or cerebellum. A dual TPP-I- and beta-galactosidase-expressing adenovirus vector (AdTTP-I/nlsbetagal) was used to distinguish transduced (beta-galactosidase positive) cells from cells that endocytosed secreted TTP-I. Ten days after striatal injection of AdTTP-I/nlsbetagal, beta-galactosidase-positive cells were concentrated around the injection site, corpus callosum, ependyma and choroid plexus. In cerebellar injections, beta-galactosidase expression was confined to the region of injection and in isolated neurons of the brainstem. Immunohistochemistry for TPP-I expression showed that TPP-I extended beyond areas of beta-galactosidase activity. Immunohistochemistry for TTP-I after FIVTTP-I and AAV5TTP-I injections demonstrated TPP-I in neurons of the striatum, hippocampus and Purkinje cells. For all three vectors, TPP-I activity in brain homogenates was 3-7-fold higher than endogenous levels in the injected hemispheres. Our results indicate the feasibility of vector-mediated gene transfer of TPP-I to the CNS as a potential therapy for LINCL.

Adenoviridae↗
PubMed2003

Comparison of ximelagatran, an oral direct thrombin inhibitor, with enoxaparin for the prevention of venous thromboembolism following total hip replacement. A randomized, double-blind study.

BACKGROUND: Prophylaxis is recommended following total joint replacement because of the high risk of venous thromboembolism (VTE). Postoperative low-molecular-weight heparin (LMWH) reduces the incidence of venographically detected deep vein thrombosis (DVT) to about 10-15% in total hip replacement (THR) patients. Ximelagatran is a novel, oral direct thrombin inhibitor that selectively and competitively inhibits both free and clot-bound thrombin. We compared the efficacy and safety of ximelagatran with those of enoxaparin for the prevention of VTE in patients undergoing THR. METHODS: This was a prospective, randomized, multicenter, double-blind study conducted principally in the USA and Canada. Patients received fixed-dose oral ximelagatran 24 mg bid or subcutaneous enoxaparin 30 mg bid and matched placebo for 7-12 days; both regimens were initiated the morning after surgery. The incidence of VTE (by postoperative day 12) included thrombosis determined by mandatory venography of the leg on which surgery was performed and symptomatic, objectively proven DVT or pulmonary embolism (PE). VTE and bleeding events were interpreted by an independent central adjudication committee for primary analysis. RESULTS: Of the 1838 patients randomized, 1557 had either adequate venography or symptomatic, proven VTE (efficacy population). Overall rate of venography acceptable for evaluation was 85.4%. Overall rates of total VTE were 7.9% (62 of 782 patients) in the ximelagatran group and 4.6% (36 of 775 patients) in the enoxaparin group, with an absolute difference of 3.3% and a 95% confidence interval for the difference of 0.9% to 5.7%. Proximal DVT and/or PE occurred in 3.6% (28 of 782 patients) in the ximelagatran group and 1.2% (nine of 774 patients) in the enoxaparin group. Major bleeding events were observed in 0.8% (seven of 906) of the ximelagatran-treated patients and in 0.9% (eight of 910) of the enoxaparin-treated patients (P > 0.95). Non-inferiority of ximelagatran 24 mg bid based on a prespecified margin of 5% was not met, resulting in superiority of the enoxaparin regimen. CONCLUSIONS: Both ximelagatran and enoxaparin decreased the overall rate of VTE compared with that reported historically. However, in this study, enoxaparin 30 mg bid was more effective than ximelagatran 24 mg bid for prevention of VTE in THR. Oral ximelagatran was used without coagulation monitoring, was well tolerated, and had bleeding rates comparable to those of enoxaparin. Further refinement by testing a higher dose of ximelagatran in the patients undergoing THR is warranted.

Administration, Oral↗
PubMed2002

Apical barriers to airway epithelial cell gene transfer with amphotropic retroviral vectors.

Gene transfer to airway epithelia with amphotropic pseudotyped retroviral vectors is inefficient following apical vector application. To better understand this inefficiency, we localized the expression of Pit2, the amphotropic receptor, in polarized human airway epithelia. Pit2 was expressed on both the apical and basolateral surfaces of the cells, suggesting that factors other than receptor abundance may limit apical gene transfer efficiency. Binding studies performed with radiolabeled amphotropic MuLV suggested that the apically applied virus binds to Pit2. Hypothetical barriers to retroviral gene transfer include the apical glycocalyx and other secreted products of epithelia. In this study, we demonstrated that sialic acid, keratan sulfate and collagen type V are present on the apical surface of well-differentiated human airway epithelia. While enzyme treatment reduced the abundance of these components, the treatment also decreased the transepithelial resistance to approximately 35% of the controls, suggesting that the epithelial integrity was impaired. To attain an airway epithelial culture with a modified apical surface and intact epithelial integrity, we utilized 100 mM 2-deoxy-D-glucose, a glycosylation inhibitor, to prevent the glycocalyx from reforming following enzyme treatment. This approach allowed the resistance, but not the apical glycocalyx to recover. Despite this physical modification of the cell surface, the amphotropic retroviral vector failed to transduce airway epithelia following apical application. These results suggest that factors other than apical receptor abundance and the glycocalyx inhibit amphotropic retroviral gene transfer in human airway epithelia.

Cell Polarity↗
PubMed2001

Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease.

BACKGROUND: Low-molecular-weight heparins administered subcutaneously once or twice daily have been reported to be as safe and efficacious as intravenous unfractionated heparin in the treatment of acute venous thromboembolic disease. OBJECTIVE: To determine whether subcutaneous enoxaparin administered once or twice daily is as effective as continuously infused unfractionated heparin in acute symptomatic venous thromboembolic disease. DESIGN: Randomized, controlled, partially blinded equivalence trial. SETTING: 74 hospitals in 16 countries. PATIENTS: 900 patients with symptomatic lower-extremity deep venous thrombosis, including 287 (32%) with confirmed pulmonary embolism. INTERVENTIONS: Initial therapy with dose-adjusted intravenous unfractionated heparin compared with subcutaneous enoxaparin at fixed dosages of 1.0 mg/kg of body weight twice daily or 1.5 mg/kg once daily. Long-term oral anticoagulation was started in all patients within 72 hours of randomization. MEASUREMENTS: Clinical end points assessed during a 3-month follow-up period. RESULTS: Equivalent efficacy was seen in the heparin group and both enoxaparin groups. Symptomatic venous thromboembolism recurred in 12 of 290 patients receiving unfractionated heparin (4.1%), 13 of 298 patients receiving once-daily enoxaparin (4.4%), and 9 of 312 patients receiving twice-daily enoxaparin (2.9%). Compared with unfractionated heparin, the treatment difference was 0.2% (95% CI, -3.04% to 3.49%) for once-daily enoxaparin and -1.2% (CI, -4.2% to 1.7%) for twice-daily enoxaparin. Incidence of major hemorrhage did not differ among the three treatment groups. Major hemorrhage occurred in 6 of 290 patients (2.1%) in the unfractionated heparin group, 5 of 298 patients (1.7%) in the once-daily enoxaparin group, and 4 of 312 patients (1.3%) in the twice-daily enoxaparin group. CONCLUSIONS: Subcutaneous enoxaparin once or twice daily is as effective and safe as dose-adjusted, continuously infused unfractionated heparin in the prevention of recurrent symptomatic venous thromboembolic disease.

Administration, Cutaneous↗
PubMed2001

Non-secretion of mutant proteins of the glaucoma gene myocilin in cultured trabecular meshwork cells and in aqueous humor.

Until recently, very little was known about the molecular mechanisms responsible for the development of glaucoma, a leading cause of blindness worldwide. Mutations in the glaucoma gene myocilin (MYOC, GLC1A) are associated with elevated intraocular pressure and the development of autosomal dominant juvenile glaucoma and a subset of adult-onset glaucoma. MYOC is expressed in the trabecular meshwork (TM), a tissue responsible for drainage of aqueous humor from the eye, and the tissue involved in elevated intraocular pressure associated with glaucoma. To better understand the role of MYOC in glaucoma pathogenesis, we examined the expression of normal and mutant myocilin in cultured ocular (TM) and non-ocular cells as well as in the aqueous humor of patients with and without MYOC glaucoma. Normal myocilin was secreted from cultured cells, but very little to no myocilin was secreted from cells expressing five different mutant forms of MYOC. In addition, no mutant myocilin was detected in the aqueous humor of patients harboring a nonsense MYOC mutation (Q368X). Co-transfection of cultured cells with normal and mutant myocilin led to suppression of normal myocilin secretion. These studies suggest that MYOC glaucoma is due either to insufficient levels of secreted myocilin or to compromised TM cell function caused by congestion of the TM secretory pathway.

Animals↗
PubMed2001

Adenovirus-mediated gene delivery to cells of the magnocellular hypothalamo-neurohypophyseal system.

The objective of the present study was to define the optimum conditions for using replication-defective adenovirus (Ad) to transfer the gene for the green fluorescent protein (GFP) to the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei and cells of the neurohypophysis (NH). As indicated by characterizing cell survival over 15 days in culture and in electrophysiological whole cell patch-clamp studies, viral concentrations up to 2 x 10(7) pfu/coverslip did not affect viability of transfected PVN and NH cultured cells from preweanling rats. At 2 x 10(7) pfu, GFP gene expression was higher (40% of GFP-positive cells) and more sustained (up to 15 days). Using a stereotaxic approach in adult rats, we were able to directly transduce the PVN, SON, and NH and visualize gene expression in coronal brain slices and in the pituitary 4 days after injection of Ad. In animals receiving NH injections of Ad, the virus was retrogradely transported to PVN and SON neurons as indicated by the appearance of GFP-positive neurons in cultures of dissociated cells from those brain nuclei and by polymerase chain reaction and Western blot analyses of PVN and SON tissues. Adenoviral concentrations of up to 8 x 10(6) pfu injected into the NH did not affect cell viability and did not cause inflammatory responses. Adenoviral injection into the pituitary enabled the selective delivery of genes to the soma of magnocellular neurons. The experimental approaches described here provide potentially useful strategies for the treatment of disordered expression of the hormones vasopressin or oxytocin.

Adenoviridae↗
PubMed2001

Infection of human airway epithelia with H1N1, H2N2, and H3N2 influenza A virus strains.

Three subtypes of influenza A virus cause human disease: H1N1, H2N2, and H3N2. Although all result in respiratory illness, little is known about how these subtypes infect differentiated airway epithelia. Therefore, we assayed A/PR/8/34 (H1N1), A/Japan/305/57 (H2N2), and X31 (H3N2) influenza virus strains for binding and infection on fully differentiated primary cultures of airway epithelia isolated from human bronchus, grown on semiporous filters at an air-liquid interface. In this model system, viral infectivity was highest when virus was applied to the apical versus the basolateral surface; Japan was most infectious, followed by PR8. The X31 strain showed very low levels of infectivity. Confocal microscopy and fluorescence-resonance energy transfer studies indicated that Japan virus could enter and fuse with cellular membranes, while infection with X31 virions was greatly inhibited. Japan virus could also productively infect human trachea explant tissues. These data show that influenza viruses with SAalpha2,3Gal binding specificity, like Japan, productively infect differentiated human airway epithelia from the apical surface. These data are important to consider in the development of pseudotyped recombinant viral vectors for gene transfer to human airway epithelia for gene therapy.

Antibodies, Viral↗
PubMed2001

In vivo treatment of hemophilia A and mucopolysaccharidosis type VII using nonprimate lentiviral vectors.

Gene therapy holds great promise for the treatment of a variety of inherited diseases, including hemophilia A and mucopolysaccharidosis type VII (MPS VII). In both these disorders, subnormal levels of replacement protein have therapeutic effects. Thus we hypothesized that transduction of a small proportion of cells by feline immunodeficiency virus (FIV)-based lentiviral vectors might provide sufficient levels of transgene expression for phenotypic correction. We intravenously injected replication-deficient FIV-based vectors encoding either human factor VIII or human beta-glucuronidase into factor VIII-deficient or beta-glucuronidase-deficient mice, respectively. This route of delivery targeted multiple organs, with the liver as the primary transduction site. In the hemophilia A mice, factor VIII expression persisted for the duration of the experiments (approximately 5 months), and recipient mice survived an otherwise lethal bleeding episode (tail-clipping). In mucopolysaccharidosis type VII mice, substantial beta-glucuronidase activity was detected in several tissues and corresponded with marked reduction of lysosomal storage in liver and spleen. These findings indicate that gene transfer with FIV-based lentiviral vectors can permanently introduce transgenes into a sufficient number of hepatocytes for long-term therapeutic effect and suggest potential clinical value of FIV-based lentiviral vectors for treatment of hemophilia A and MPS VII.

Animals↗
PubMed2001

The HIV Tat protein transduction domain improves the biodistribution of beta-glucuronidase expressed from recombinant viral vectors.

Treatment of inherited genetic diseases of the brain remains an intractable problem. Methods to improve the distribution of enzymes that are injected or expressed from transduced cells will be required for many human brain therapies. Recent studies showed that a peptide, the protein transduction domain (PTD) from HIV Tat, could improve the distribution of cytoplasmic reporter proteins when administered systemically as fusion proteins or cross-linked chimeras. The utility of this motif for noncytoplasmic proteins has not been determined. Here, we tested how the Tat motif affected uptake and biodistribution of the lysosomal enzyme beta-glucuronidase, the protein deficient in the disease mucopolysaccharidosis VII, when expressed from viral vectors. The Tat motif allowed for mannose-6-phosphate (M6P) independent uptake in vitro and significantly increased the distribution of beta-glucuronidase secreted from transduced cells after intravenous or direct brain injection in mice of recombinant vectors. Thus, enzymes modified to contain protein transduction motifs may represent a general strategy for improving the distribution of secreted proteins following in vivo gene transfer.

3T3 Cells↗
PubMed2001

Adenoviral gene transfer restores lysyl hydroxylase activity in type VI Ehlers-Danlos syndrome.

Type VI Ehlers-Danlos syndrome is a disease characterized by disturbed lysine hydroxylation of collagen. The disease is caused by mutations in lysyl hydroxylase 1 gene and it affects several organs including the cardiovascular system, the joint and musculoskeletal system, and the skin. The skin of type VI Ehlers-Danlos syndrome patients is hyperelastic, scars easily, and heals slowly and poorly. We hypothesized that providing functional lysyl hydroxylase 1 gene to the fibroblasts in and around wounds in these patients would improve healing. In this study we tested the feasibility of transfer of the lysyl hydroxylase 1 gene into fibroblasts derived from rats and a type VI Ehlers-Danlos syndrome patient (in vitro) and into rat skin (in vivo). We first cloned human lysyl hydroxylase 1 cDNA into a recombinant adenoviral vector (Ad5RSV-LH). Transfection of human type VI Ehlers-Danlos syndrome fibroblasts (about 20% of normal lysyl hydroxylase 1 activity) with the vector increased lysyl hydroxylase 1 activity in these cells to near or greater levels than that of wild type, unaffected fibroblasts. The adenoviral vector successfully transfected rat fibroblasts producing both beta-galactosidase and lysyl hydroxylase 1 gene activity. We next expanded our studies to a rodent model. Intradermal injections of the vector to the abdominal skin of rats produced lysyl hydroxylase 1 mRNA and elevated lysyl hydroxylase 1 activity, in vivo. These data suggest the feasibility of gene replacement therapy to modify skin wound healing in type VI Ehlers-Danlos syndrome patients.

Adenoviridae↗
PubMed2001

Vascular cell adhesion molecule-1 augments adenovirus-mediated gene transfer.

We have reported that adenovirus-mediated gene transfer is augmented in the endothelium of atherosclerotic blood vessels. We observed that vascular cell adhesion molecule-1 (VCAM-1) shares some homology with the coxsackievirus and adenovirus receptor. Because VCAM-1 is upregulated on atherosclerotic endothelial cells, we hypothesized that VCAM-1 may act as an auxiliary receptor to augment adenovirus-mediated gene transfer. To test this hypothesis, stable NIH 3T3 cell lines that constitutively express VCAM-1 on the cell surface were generated. Recombinant adenovirus 5 (Ad5), which contains the reporter ss-galactosidase gene, was used to compare Ad5 infection in VCAM-1(+) and parental NIH 3T3 cells. Total ss-galactosidase activity and the number of transgene-positive cells were 6- to 10-fold and 5-fold higher, respectively, in VCAM-1(+) than in VCAM-1(-) cells. Ad5 binding to VCAM-1(+) cells was increased by 3-fold over VCAM-1(-) cells. Soluble VCAM-1 protein, present during infection or viral binding, reduced ss-galactosidase activity in VCAM-1(+) cells in a dose-dependent manner. Taken together, we conclude that VCAM-1 can mediate adenovirus binding and infection. This may explain, in part, the previous finding that adenovirus-mediated gene transfer is augmented in atherosclerotic arteries.

3T3 Cells↗