Recombinant adenovirus (rAd) and recombinant adeno-associated virus (rAAV) are among the most extensively used vectors in gene therapy studies to date. These two vectors share some similar features such as a broad host range and ability to infect both proliferating and quiescent cells. However, they also possess their own unique set of properties that render them particularly attractive for gene therapy applications. rAd vectors can accommodate larger inserts, mediate transient but high levels of protein expression, and can be easily produced at high titers. Development of gutted rAd vectors has further increased the cloning capacity of these vectors. The gaining popularity of rAAV use in gene therapy can be attributed to its lack of pathogenicity and added safety due to its replication defectiveness, and its ability to mediate long-term expression in a variety of tissues. Site-specific integration, as occurs with wild-type AAV, will be a unique and valuable feature if incorporated into rAAV vectors, further improving their safety. This paper describes these properties of rAd and rAAV vectors, and discusses further development and vector improvements that continue to extend the utility of these vectors, such as cell retargeting by capsid modification, differential transduction by use of serotypes, and extension of the cloning capacity of rAAV vectors by dual vector heterodimerization.

Adenovirus and adeno-associated virus vectors

IS-12 Mutation and altered expression of P16^ in human cancer.

Cancer gene therapy has been one of the most exciting areas of therapeutic research in the past decade. In this review, we discuss strategies to restrict transcription of transgenes to tumour cells. A range of promoters which are tissue-specific, tumour-specific, or inducible by exogenous agents are presented. Transcriptional targeting should prevent normal tissue toxicities associated with other cancer treatments, such as radiation and chemotherapy. In addition, the specificity of these strategies should provide improved targeting of metastatic tumours following systemic gene delivery. Rapid progress in the ability to specifically control transgenes will allow systemic gene delivery for cancer therapy to become a real possibility in the near future.

/pdf/transcriptional-targeting-in-cancer-gene-therapy-2j3khrnsp4.pdf

Transcriptional Targeting in Cancer Gene Therapy.

The potential use of adenoviruses in therapy against cancer has evoked a rapidly moving field of research. Unlike conventional gene therapy vectors, oncolytic adenoviruses retain the ability to replicate. However, replication is restricted as much as possible to tumor cells, with the aim of eliminating these cells through viral cytotoxicity. The two key issues are to improve the efficiency of virus replication and cell killing while ensuring the specificity of these activities for tumor cells. Wild-type adenoviruses as such may already be usable for cancer therapy. Strategies to further improve efficiency and specificity include the partial or complete removal of viral genes. The idea is that functions carried out by the corresponding gene products are not required for replication in tumor cells, but are needed in normal cells. Accordingly, the removal of genes encoding E1B-55 kDa or E1B-19 kDa, or the mutation of E1A may improve the selective killing of tumor cells. On the other hand, the overexpression of the adenovirus death protein (ADP) may enhance viral spread and oncolytic efficiency. Other strategies to improve the specific oncolytic activity of replicating adenoviruses have been pursued. For instance, some promoters are active specifically in tumor cells, and these promoters were introduced into the viral genome, to regulate essential viral genes. Moreover, replicating viruses were engineered to express toxic proteins or drug converters. A number of these viruses have been tested successfully using tumor xenografts in nude mice as a model system. An oncolytic adenovirus lacking the E1B-55 kDa gene product, termed d11520 or ONYX015, was injected into squamous cell carcinomas of head and neck in phase II clinical trials, and the results were encouraging when chemotherapy was applied in parallel. In the future, further progress might be achieved on the level of virus constructs, but also by refining and adjusting simultaneous conventional therapies, and by standardizing the assessment of the clinical outcome.

Replicating adenoviruses in cancer therapy.

Gene-viral therapy, which uses replication-selective transgene-expressing viruses to manage tumors, can exploit the virtues of gene therapy and virotherapy and overcome the limitations of conventional gene therapy. Using a human telomerase reverse transcriptase-targeted replicative adenovirus as an antiangiogenic gene transfer vector to target new angiogenesis and making use of its unrestrained proliferation are completely new concepts in tumor management. CNHK300-mE is a selective replication transgene-expressing adenovirus constructed to carry mouse endostatin gene therapeutically. Infection with CNHK300-mE was associated with selective replication of the adenovirus and production of mouse endostatin in telomerase-positive cancer cells. Endostatin secreted from a human gastric cell line, SGC-7901, infected with CNHK300-mE was significantly higher than that infected with nonreplicative adenovirus Ad-mE in vitro (800 +/- 94.7 ng/ml versus 132.9 +/- 9.9 ng/ml) and in vivo (610 +/- 42 ng/ml versus 126 +/- 13 ng/ml). Embryonic chorioallantoic membrane assay showed that the mouse endostatin secreted by CNHK300-mE inhibited angiogenesis efficiently and also induced distortion of pre-existing vasculature. CNHK300-mE exhibited a superior suppression of xenografts in nude mice compared with CNHK300 and Ad-mE. In summary, we provided a more efficient gene-viral therapy strategy by combining oncolysis with antiangiogenesis.

https://cancerres.aacrjournals.org/content/canres/64/15/5390.full.pdf

Effective Gene-Viral Therapy for Telomerase-Positive Cancers by Selective Replicative-Competent Adenovirus Combining with Endostatin Gene

Target gene therapy for alpha-fetoprotein-producing hepatocellular carcinoma by E1B55k-attenuated adenovirus.

The immune defense system in the liver is known to consist of Kupffer cells, pit cells, lymphocytes, neutrophils, and other infiltrating immune responsive cells. In the liver, Kupffer cells as well as pit cells play an important role in tumor defense and the immune surveillance system. Activation of these cells could contribute to cytotoxicity against tumor cells. In an experimental model of hepatic metastasis of colon carcinoma, biological response modifiers potentially activate these immune responsive cells and reduce hepatic metastasis of tumor cells. Since the activation of pit cells may be induced by interleukin-2 (IL-2), the local tumor surveillance system of the liver can be activated by gene transduction of IL-2 cDNA in hepatocytes using adenovirus vector. Local production of IL-2 may enhance the natural killer (NK) activity of pit cells, leading to a reduction of hepatic metastasis of colon carcinoma. The modulation of sinusoidal cells by gene transduction (gene therapy) may provide a tool to change the pathophysiology of the liver, leading to a clinical treatment for liver diseases.

Modulation of Hepatic Sinusoidal Cell Function by Transduction of Genes in the Liver: Gene Therapy for Hepatic Micro-Metastasis

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Target gene therapy for alpha-fetoprotein-producing hepatocellular carcinoma by E1B55k-attenuated adenovirus.

Modulation of Hepatic Sinusoidal Cell Function by Transduction of Genes in the Liver: Gene Therapy for Hepatic Micro-Metastasis