Reports of Adenovector “Death” Are Greatly Exaggerated
Authors: Malcolm Brenner
Journal: Molecular Therapy (2000)

For clinical gene therapy in general, and adenoviral vectors in particular, it has been a brutal 6 months. To the sense of disappointment about the lack of clear-cut clinical success was added the upset of Jesse Gelsinger's death after injection of an adenovector intended to help correct his ornithine transcarbamylase deficiency. Worsening an already bad situation was the widely reported—and rapidly rebutted—false alarm of HIV/HCV contamination of an adenovector used to prepare a tumor vaccine for advanced relapsed neuroblastoma patients. Given these sad events, many are asking if adenovectors have any place in gene therapy. There is little doubt that the major concern over adenovectors is their potential toxicity. Although the exact cause of Gelsinger's death may never be determined, it probably relates to one or more of the toxicities seen in animal models. During the first few hours of infection, the adenovector proteins provoke an acute phase immune response, marked by rapid release of inflammatory cytokines and recruitment of host cellular defenses. Over the next 24–96 h, most of the vector-associated toxicity can be attributed to cellular production of adenoviral coat-assembly proteins. Subsequently, the immune system recognizes and destroys adenoviral peptides on the surface of infected cells, and this late phase toxicity may be related to hepatocyte hypertrophy and hepatic fibrosis. Efforts to reduce adenoviral toxicity have focused on making increasingly extensive deletion mutants that reduce viral protein production by infected cells. The ultimate attenuated adenovector is the so-called helper-dependent or “gutless” vector, in which virtually all of the adenoviral genes are removed and replaced with the gene of interest, its promoter, and irrelevant DNA to allow packaging in the viral envelope. The “helper” adenovector must then be separated from the deleted vector. Helper-dependent vectors have a much higher therapeutic index than conventional adenovectors in several different models. They also appear much less immunogenic, so that transduced postmitotic cells may secrete vector-derived proteins over many months—a primary consideration in the treatment of many deficiency disorders. However, these vectors are proving quite difficult to manufacture in adequate quantities for human trials. Furthermore, they likely remain nonintegrating and do not replicate as episomes, so that transduction of rapidly dividing tissues, e.g., hemopoietic stem cells, is feasible only when short-term gene expression is desired. Modification of cell targeting may increase the safety and efficiency of adenovectors in addition to gene removal, but this is still unknown. Given these liabilities, do adenovectors belong in the clinic? The narrow therapeutic index, the short duration of expression, and the immunogenicity of E-region-deleted vectors mean that current adenovectors are not suitable for protein replacement therapy in genetic diseases. However, they are particularly well suited to cancer gene therapy. Because they transduce many different cell types with relatively high efficiency, they can transfer toxic or immunomodulatory genes to a broad spectrum of tumors, both ex vivo and locally in vivo. As the aim of cancer gene therapy is to kill tumor cells, the limited duration of transgene expression is not necessarily a problem. In addition, inducing a destructive immune response against the transduced cell and the transgene product can be an advantage. Most adenoviral cancer gene therapy approaches to date have not produced significant toxicity, and the fact that they appear non-cross-reactive with cytotoxic drugs or radiation significantly increases the number of treatment options. Although they are not suitable for some gene therapy approaches, it is clear that reports of the death of adenovectors are greatly exaggerated. Once the detrimental media feeding frenzy finally passes, they will “rise from the dead” to make substantial contributions to the success of gene therapy. This Editorial is identified by doi:10.1006/mthe.2000.0047.