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    Expression of an engineered soluble Coxsackievirus and Adenovirus Receptor by a dimeric AAV9 vector inhibits Adenovirus infection in mice (2015)

    Art
    Poster
    Autoren
    Roger, C
    Pozzuto, T
    Klopfleisch, R (WE 12)
    Kurreck, J
    Fechner, H
    Pinkert, S
    Kongress
    Collaborative Congress of the European­ Society­ of ­Gene­ & Cell­ Therapy (ESGCT) and Finnish­ Society ­of­ Gene­ Therapy (FSGT)
    Helsinki, Finnland, 17. – 20.09.2015
    Quelle
    Gene therapy; 22(6) — S. 458–466
    ISSN: 0969-7128
    Verweise
    URL (Volltext): http://www.nature.com/doifinder/10.1038/gt.2015.19
    DOI: 10.1038/gt.2015.19
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    Abstract / Zusammenfassung

    Immunosuppressed (IS) patients, such as recipients of hematopoietic stem cell transplantation, occasionally develop severe and fatal adenovirus (Ad) infections. Here, we analyzed the potential of a virus receptor trap based on a soluble coxsackievirus and Ad receptor (sCAR) for inhibition of Ad infection. In vitro, a dimeric fusion protein, sCAR-Fc, consisting of the extracellular domain of CAR and the Fc portion of human IgG1 and a monomeric sCAR lacking the Fc domain, were expressed in cell culture. More sCAR was secreted into the cell culture supernatant than sCAR-Fc, but it had lower Ad neutralization activity than sCAR-Fc. Further investigations showed that sCAR-Fc reduced the Ad infection by a 100-fold and Ad-induced cytotoxicity by ~20-fold. Not only was Ad infection inhibited by sCAR-Fc applied prior to infection, it also inhibited infection when used to treat ongoing Ad infection. In vivo, sCAR-Fc was delivered to IS mice by an AAV9 vector, resulting in persistent and high (>40 μg ml−1) sCAR-Fc serum levels. The sCAR-Fc serum concentration was sufficient to significantly inhibit hepatic and cardiac wild-type Ad5 infection. Treatment with sCAR-Fc did not induce side effects. Thus, sCAR-Fc virus receptor trap may be a promising novel therapeutic for treatment of Ad infections.