Viral gene therapy strategies: from basic science to clinical application

Abstract

A major impediment to the successful application of gene therapy for the treatment of a range of diseases is not a paucity of therapeutic genes, but the lack of an efficient nontoxic gene delivery system. Having evolved to deliver their genes to target cells, viruses are currently the most effective means of gene delivery and can be manipulated to express therapeutic genes or to replicate specifically in certain cells. Gene therapy is being developed for a range of diseases including inherited monogenic disorders and cardiovascular disease, but it is in the treatment of cancer that this approach has been most evident, resulting in the recent licensing of a gene therapy for the routine treatment of head and neck cancer in China. A variety of virus vectors have been employed to deliver genes to cells to provide either transient (eg adenovirus, vaccinia virus) or permanent (eg retrovirus, adeno-associated virus) transgene expression and each approach has its own advantages and disadvantages. Paramount is the safety of these virus vectors and a greater understanding of the virus-host interaction is key to optimizing the use of these vectors for routine clinical use. Recent developments in the modification of the virus coat allow more targeted approaches and herald the advent of systemic delivery of therapeutic viruses. In the context of cancer, the ability of attenuated viruses to replicate specifically in tumour cells has already yielded some impressive results in clinical trials and bodes well for the future of this approach, particularly when combined with more traditional anti-cancer therapies.

Ultrasound-assisted non-viral gene transfer to the salivary glands

“…6 Viral vectors have clearly proven the principle that gene transfer to the salivary glands has the potential to transform many facets of oral medicine, but viral vector technology has drawbacks. 7 Despite significant progress, viral vectors elicit host immune responses, [8][9][10] can pose onocogenic risks 11,12 and cannot achieve life-long expression in vivo.…”

Oncolytic virus therapy for pancreatic cancer using the adenovirus library displaying random peptides on the fiber knob

“…The key prerequisite for an efficient oncolytic virus is the restriction of virus replication in tumor cells, and, so far, two major approaches have been examined for an oncolytic adenovirus: genetic complementation type (Type I) has a mutation in the E1 region, and the transcomplementation type (Type II) is designed to harbor a tumor/tissue-specific promoter in the upstream of the E1 gene. 2,3 Although the replication and spreading of such CRAds are restricted to tumor tissue in theory, several levels of additional safety devices are definitely required: the engineering of an adenovirus capsid to restrict infection for tumor cells is the first safety device and E1 manipulation to limit replication in the tumors is the second safety device.…”

“…[1][2][3] For this purpose, the variety of oncolytic viruses such as adenovirus, herpes simplex virus, influenza virus, Newcastle disease virus, poliovirus, reovirus, vaccinia virus and vesicular virus have been developed. 1,3 In the context of conditionally replicative adenoviruses (CRAds), two strategies have been employed to restrict virus replication to target cells. One strategy is to introduce a mutation in the E1 region, and the function of these missing genes may be complemented by genetic mutation in tumor cells such as p53 mutation.…”

“…An alternative strategy is to construct viruses in which the transcription of E1 genes is restricted to tumor cells by either a tumor or a tissuespecific promoter. 2,3 However, a leak of an oncolytic adenovirus from the virus-replicating tumors into systemic circulation often causes ectopic transduction of vital organs such as the liver. 2 Therefore, the suppression of naive viral tropism is needed to reduce the undesirable infection of nontarget normal tissues.…”

In vitro and in vivo delivery of novel anticancer fusion protein MULT1E/FasTI via adenoviral vectors

“…At present, adenoviruses are still an attractive vector to deliver desirable genes for the treatment of cancer because of its high infectivity in vivo, which allows for direct vector injection in the clinic, and avoids additional manipulations in vitro as required for other vector systems such as retroviruses. 25 The most encouraging preclinical finding from our study is that mice that received treatment with the Ad-MULTE/ FasTI fusion construct showed more apoptosis in vivo and formed smaller tumors.…”