Adenovirus-based Gene Therapy: a Promising Novel Cancer Therapy

A Viral Biorealm page on the family Adenovirus-based Gene Therapy: a Promising Novel Cancer Therapy

Adenovirus: Group I, dsDNA
Family: Adenoviriade
Genera: Atadenovirus, Aviadenovirus, Ichtadenovirus, Mastadenovirus Siadenovirus
Adenovirus structure is characterized by medium size (90-100nm), non-enveloped icosahedral, including a nucleocapsid and double stranded linear DNA genome. About 57 serotypes exist in humans and cause 5-10% of upper respiratory infections in children; it is also highly prevalent in adults. Adenoviruses infect various species of vertebrates and were first found and isolated in human adenoids in the mid 1950s.

Adenovirus is Key Component: Benefits and Risk Factors

Adenovirus (Ad) based cancer gene therapy is an innovative and novel treatment in treating severe and unresponsive cancer today. Gene therapy is a new approach to traditional therapies to combat severe forms of cancer. Gene delivery is used to “correct” and rebuild broken down and infected tissue. Ad is highly coveted for its ability to effectively tansduce cells both dividing and non-dividing, its flexibility and ability to produce high titers. Infection of Ad is mediated by the binding of the fiber knob region to the receptor of target cell, coxsackie-Ad receptor (CAR), for most serotypes in Ad, most commonly serotype 5. Entry and internalization of the virus is mediated by an interaction between the penton-base Arg-Gly-Asp (RGD) and cellular αvβ integrins, leading to the endocytosis of viron through clathrin-coated pits. The virus disassembles in the endosome while the viral DNA is transported to the nucleus. Resulting in expression of viral genes or transgenes. Ad DNA is not integrated in the host genome so the risk of mutagenosis is extremely low.

Secondary receptor interactions, heparan sulfate proteoglycans (HSPGs) have also been reported. Expression of CAR is rate-limiting factor for infectivity with Ad5 and is highly variable in primary human tumor cells. This loss of CAR expression may be due to the progression of malignant tumors and its aggressiveness. CAR is localized within tight junctions, playing a role in cell adhesions. Ad vectors have been used for many gene therapy applications. There has been little experimental data of gene transfer with Ad, giving little evidence to significant benefits, with only Phase I and II trials to date. Many approaches to other targets and capsid modifactions are also being researched.

Ad infection enlists a wide variety of immune response both humoral and cellular, towards Ad and already infected cells. Activation of the immune system allows for a natural response to combat tumor antigens but is risky in that too high a dose will result in acute toxicity and autoimmunity. To date, side effects have been mild in Ad therapy, yet non-target side effects are consistently be monitored, both long and short term in patients.

Researchers are currently trying to increase the Ad gene transfer vectors target to tumor cells and decrease any targeting to the liver. There are a number of methods currently being solicited including: Ad fiber pseudotyping, or an alteration of virus tropism through the substitution of receptor binding-proteins with those from other serotypes, for example, the substitution of Ad5 with a knob from Ad serotype 3 (Ad3). Experiments with the Ad5/3 chimeras have showed enhanced infectivity in cancer cells without increasing gene delivery to murine liver.

Respiratory tract infections are a result from droplet inhalation, while gastrointestinal problems are due to fecal-oral transmission. There are 3 different types of infections that can occur during infection. A lytic infection occurs when the adenovirus enters human epithelial cells and continues through an entire replication cycle, with a host inflammatory response. Chronic or latent infection can also occur, infecting the lymphoid tissue, and involves no symptoms. The exact mechanism is unknown.

The last interaction that can occur is oncogenic, as adenovirus integrates its own DNA into host DNA and can produces E1A proteins, altering transcription, deregulating apoptosis and forming malignant.