Gene Therapy Vectors For Gliomas


Retroviral vectors are RNA viruses converted to DNA by one of the viral enzymes (reverse transcriptase) and then integrated into the host genome at nonspecific sites. With the exception of lentiviruses, retroviruses only integrate into the genomes of rapidly dividing cells, providing an element of tumor selectivity. Most retroviral vectors are derived from the Moloney murine leukemia virus (Mo-MLV), originally developed by Mulligan and Berg in 1981 (4). Retro-virus vectors are generated in vector-producer cells (VPCs), and then they can be harvested from the medium of VPCs at titers of 105-107 PFU/mL. However, the viral particles themselves are usually too unstable to be injected directly into tumors. Thus, the transfected VPCs must be engrafted into the tumor.

The disadvantages of retroviral vector systems are: (1) low titers; (2) the need to engraft VPCs, which cannot survive for long periods; (3) low transgene capacity—the maximum amount of DNA that can be packaged into a retrovirus allows for only 8 kb of foreign DNA in the vector; and (4) risk of insertional mutagenesis if integration disrupts a protooncogene. Possible advantages include: (1) integration into dividing cells, allowing long-term gene expression, although long-term gene expression carries with it long term concerns about safety; and (2) relatively little toxicity because of replication deficiency with minimal risk of wild-type virus generation and minimal inflammation. Retro-viruses have and are being used in 54% of brain tumor gene therapy clinical trials (3).


Adenoviruses are nonenveloped DNA viruses causing upper respiratory tract infections. The adenovirus vectors used for gene delivery are derived from subgroup C. Wild-type subgroup C causes a mild upper respiratory infection, which resolves uneventfully in healthy individuals. In an adenoviral vector, the desired transgene is cloned into the E1 gene, thus disrupting it. This gene is essential for adenoviral replication, thus rendering the vector now safe to use because it will grow/replicate in infected cells but will only deliver the transgene.

High titers (up to 1012 particles/mL) can be achieved with adenovirus. Limitations include the fact that the viral genome is maintained as an extrachromosomal element that is rapidly lost in dividing cells and the highly immunogenic nature of the vectors. The immunogenic nature of adenovirus may have con-

Table 1

General Biology, Advantages, and Disadvantages of Various Viral Vectors for Cancer Gene Therapy

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