The Necessity Of Adenovirus Retargeting

Adenovirus (Ad) has been applied for gene therapy in various applications, taking advantage of its high transduction efficiency in vivo (1). However, commonly used vectors based on Ad serotype 5 and 2 require the primary adenoviral receptor, the cox-sackie adenovirus receptor (CAR), for efficient infection and, hence, show tropism determined by the tissue distribution of the CAR expression (2-5). This characteristic of the current adenoviral vector system leads to two fundamental problems; high trans-duction of nontarget cells and low transduction of the target cells.

The first issue is transduction of unwanted cell subsets. In vivo, systemically administered adenovirus vectors (or those released from local injection sites) predominantly accumulate in the liver as a result of both CAR-dependent and -independent mechanisms, leading to strong expression of the payload gene (4-9). For some diseases like hemophilia, the expression of the transgene in the liver is desirable, because the predominant, natural production site of those proteins is the liver (10,11). However, for many diseases, which require transgene expression in target cells other than the hepato-cyte, vector absorption by the liver and the possible toxicity resulting from ectopic expression of the transgene hampers the systemic application of adenoviral vectors. This is typically the case for cancer gene therapy. If nonselective vectors are employed, for example, for systemic suicide gene therapy, the expression of the activator enzyme in the liver would lead to severe adverse effects as a result of nontarget activation of the prodrug (6,12-14). Hence, a strategy to target cytotoxic transgene expression is required.

The second problem of the current adenoviral vectors is poor transduction efficiency in the cells with low-CAR expression. In many tumors, such as in pancreatic cancers (15,18), esophageal adenocarcinoma (16,17,19) as well as gastric (20), gall bladder (21), and bile duct cancers the cells express CAR on the surface at low levels only. As a result, transduction efficiency of those cells is extremely poor with vectors that display the native tropism of wild type Ad 2 or 5. To realize the therapeutic potential of Ad vectors in these CAR-deficient tumors, the development of a retargeted vector system with a CAR-independent infection machinery is mandatory.

These limitations spur the effort to develop retargeted adenoviral vectors in order to fully take advantage of the possibilities of adenoviral vector-based gene therapies.

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