TABLE 58.1 Vectors Approved for Human Use by the U. S. Office of Biotechnology Activities




Nonviral Liposomes

Naked or particle-mediated DNA Viral

Retrovirus Adenovirus

Adeno-associated virus


No replication risk, nonimmunogenic, useful for plasmids or viruses No replication risk

Efficient transfer, manufacturing easy, most commonly used Infects nonproliferating cells, noninte-grating

Low immunogenicity, targets nonprolifer-ating cells, may have discrete genome insertion sites Targets central nervous system, low im-munogenicity

Limited efficiency

Moderate efficiency, nonspecific cell targeting

Small DNA capacity (9 kb), random DNA insertion, targets only dividing cells, replication risk

Immunogenic, small DNA capacity (7.5 kb), replication risk, repeated injections required for long-term expression

Difficult to manufacture, low titer

Difficult to manufacture, host toxicity

In preclinical trials, efficiency remains low, but expression has been noted to last for several weeks, and there has been no significant inflammatory response.

Some investigators have used electrical current (electroporation) to improve DNA (or drug) entry into tumor cells with some preliminary success. Liposomes are attractive vehicles for gene delivery, since they can carry plasmid, antisense, or viral DNA. Compared with viral approaches, however, liposomes remain relatively inefficient at facilitating gene transfer, although their safety profile remains more desirable. Some of the attributes and limitations of the nonviral methods are listed in Table 58.1.

Because viruses can efficiently integrate into the genome, many clinical trials are exploring the use of replication-defective recombinant viral vectors and delivery systems. Retroviruses contain their genetic information as a double-strand DNA genome that is transcribed, and the single-strand proviral DNA product is stably integrated into the host genome. Recombinant DNA technology has been used to remove deleterious viral genes involved in replication, and the resulting vector is replication defective, nonpathogenic, and unable to produce infectious particles. Ideally, with a retro-viral vector, only a single administration should be required because the gene should be permanently retained and expressed. No clinical evidence of mutage-nesis has emerged from the clinical trials performed to date, but the number of patients treated and the time of exposure has been limited.

Adenoviral vectors have also been used in human trials. These vectors enter cells by either an adenovirus fiber-specific receptor or a surface integrin receptor. They efficiently transfer genes in nonreplicating and replicating cells. Nonetheless, immunological responses to viruses have been noted with adenoviral vectors. Replication-selective adenovirus vectors have been introduced to optimize infection of target cells and minimize infection of normal cells. Over 200 cancer patients have been treated to date in more than 10 clinical trials with little evidence of toxicity reported. Replication, however, has generally been transient (<10 days), with limited efficacy observed when the gene therapy was administered as a single agent. More encouraging antitumor effects have been observed when the gene therapy was combined with cytotoxic chemotherapy. Further modifications are likely to be required before there can be general application of adenoviral vectors for cancer therapy.

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