In 1953, Wallace Rowe was then a postdoctoral fellow at the National Institutes of Health with Robert Huebner; they were working, with their colleagues, to isolate the “virus of the common cold.” Toward this goal, Dr. Rowe was using explants of adenoids and tonsils grown in cell culture. He...

Since Rowe et al1 first isolated adenovirus from human adenoid cells, more than 100 different species have been identified from various mammals. The family is characterized by the distinctive architecture of the virion, or virus particle, which is formed from a well defined set of structural...

The DNA genomes of adenoviruses have been the objects of intense scrutiny since the first representative of this virus family was isolated in the winter of 1953-54. Both the oncogenicity of human serotypes, first recognized in 1962, and the expression of viral genetic information via cellular RNA...

With the advent of the electron microscope, it became possible to study the entry of adenoviruses into eukaryotic cells. Time course experiments of adenovirus uptake into the cells indicated a pathway of adenovirus entry which is similar to that followed by other ligands which enter the cells by...

The major targets of human adenoviruses are terminally differentiated epithelial cells of the upper respiratory tract, gut and eye. Once the virus has entered the cell and its DNA uncoated appropriately, progression of the infectious cycle depends on the ability of the virus to solve several...

After adenovirus (Ad) enters the cell by receptor-mediated endocytosis, the viral DNA is uncoated and transported to the nucleus. Beginning at 6-8 hours post-infection, DNA is efficiently replicated, generating high amounts of progeny molecules (105-106/cell). Development of a cell-free system...

The late phase of an adenovirus infection begins with the onset of viral DNA replication. During the late phase, protein synthesis in adenovirus-infected cells is dominated by the production of large quantities of the adenovirus capsid proteins and of a few non-structural proteins required for...

With the possible exception of very simple viruses, most viruses appear to encode at least one virus-specific endopeptidase. In addition to facilitating the orchestrated fragmentation of polyproteins of RNA viruses, these proteolytic enzymes may also be involved with the suppression of host...

The assembly of adenovirus particles proceeds through an ordered series of assembly events (reviewed in ref. 1). The assembly of the virus particles has been probed using viral temperature-conditional mutants blocked at different stages of assembly at the restrictive temperature and by...

In recent years adenoviruses have been extensively used as vectors to deliver foreign genome into mammalian cells (reviewed in refs. 1-5). Adenoviruses have certain features, which make them attractive vectors for gene transfer to target cells. Some of these properties include their ability to...

Cancer can be considered a “genetic” disorder, and thus a legitimate target for gene therapy, in as much as it arises as a result of a stepwise accumulation of genetic defects in a clone of cells. In the last decade or so, several epigenetic and genetic events have been characterized that...

Cardiovascular diseases affect over 60 million people in the United States, and resulted in over 150 billion dollars in expenses in 1996 (American Heart Association, 1997). As such, the potential for clinical benefits from cardiovascular gene transfer is great and the targets for therapy are...

Neurodegenerative diseases are steadily becoming more prominent as human life expectancy increases. Gene therapy holds tremendous promise for the long term treatment of neurodegenerative disorders. The potential successes of gene therapy as a clinically useful therapeutic will be determined by...

Duchenne’s muscular dystrophy (DMD) and the less severe Becker muscular dystrophy (BMD) result from mutations in the dystrophin gene on chromosome Xp21.1 DMD, which afflicts approximately 1 in 3,500 male newborns, is fatal by the third decade of life in most patients, usually due to severe...

In the last decade adenovirus-mediated in vivo gene transfer has been effectively utilized to enhance our understanding of the role that different apolipoproteins, enzymes, receptors and transfer proteins play in lipoprotein metabolism, as well as to identify potential candidate genes that modify...

There are numerous inherited and acquired serum protein deficiencies that cause moderate to severe and even life threatening diseases in people. Some of the diseases include α1-antitrypsin deficiency, hemophilias A and B, diabetes mellitus, and anemia. A number of these diseases have been...

Several viruses can be used for the development of vectors for vaccination purposes. The human adenovirus type 2 (Ad2) and 5 (Ad5) have been used most extensively because of the greater understanding of their genome and interaction with the host cells. Nevertheless, for vaccination purposes other...

Full utility of adenoviral vectors is potentially undermined by their broad tropism profile. In this regard, for gene therapy purposes it would be desirable to derive adenoviral vectors that will accomplish gene delivery in a “targeted”, cell-specific manner. In order to restrict gene...

Among the repertoire of eukaryotic viruses that have been genetically engineered for targeting therapeutic genes to somatic cells, adenovirus has captured considerable attention since the early 1990s. And, while much can be said about the strengths and weaknesses of adenovirus vectors for human...

Transcriptionally targeted adenoviral vectors which are able to restrict and regulate the levels of expression of the therapeutic gene will have wide applicability for gene therapy. For cancer gene therapy, tumor-specific promoters could be used to drive drug sensitivity genes (e.g., HSV-tk,...

The vast majority of human cancers are incurable once metastatic. Chemotherapy and radiotherapy can induce tumor growth inhibition or regression in some cases, but solid tumor progression and resistance to these standard therapeutic modalities inevitably develops. Therefore, new agents with...

The human bone marrow produces a complex array of specialized cells designed to function in a myriad of ways. The pluripotent hematopoietic stem cell (HSC) gives rise to committed progenitors for the myeloid and lymphoid lineages. Myeloid progenitors ultimately give rise to granulocytes,...

In natural infection of humans, adenoviruses generally enter differentiated, quiescent epithelial cells. For successful propagation of virus to occur, these infected cells need to be growth stimulated. This function is performed by the concerted actions of the viral E1A and E1B gene products,...

The recent dramatic increase in the use of adenovirus as a transduction vector has led to a renewed interest in all phases of its life cycle. Among the issues that have received increased attention are those concerning the genetic integrity of the viral genome after infection into either...

With the discovery of antibiotics during World War II, the use of tissue culture soon became relatively easy after the war had ended. These findings led to the discovery of many new viruses. One of these, as described in chapter 1, was adenoviruses, in 19531 and 1954. During the period since...

Viruses have evolved ingenious mechanisms to evade the host antiviral response. The first to be recognized is antigenic variation, which allows viruses to escape preexisting antibodies, and is exemplified by influenza virus epidemics that occasionally sweep across the world. Essentially every...

Adenovirus is one of the most well-studied viruses, partly due to its use as a model of eukaryotic gene expression and partly due to efforts to develop a vaccine against outbreaks of adenovirus infection. The potential use of adenovirus for in vivo gene therapy has renewed interest in the...

Recombinant adenoviruses (Ad) are versatile gene delivery vectors capable of infecting a broad range of cell types without a requirement for cell division. They are being developed for a variety of clinical applications such as correction of inherited disorders, cancer gene therapy and treatment...

Cystic fibrosis (CF) is a recessive, monogenic, lethal disorder caused by defects in a protein termed the cystic fibrosis transmembrane conductance regulator (CFTR) . Approximately 60,000 individuals are affected worldwide. CFTR is an ion channel that functions to allow the secretion of chloride...

Our laboratory has been involved in the investigation of wild type p53 gene transfer for the selective induction of apoptosis in human upper aerodigestive tract squamous cell carcinoma of the head and neck (SCCHN). Transient overexpression of the wild type p53 gene in various malignancies has...

Malignant tumors of the liver are among the commonest cancers in the world, with an estimated annual global incidence of 1,000,000 cases per year. This includes primary tumors such as hepatocellular carcinoma (HCC) and metastases in the liver from various primary sites, for example the...

Schering-Plough Research Institute is currently sponsoring phase I/II clinical trials of adenovirus-mediated p53 gene therapy for cancer in several countries. The drug used in these clinical trials (Ad p53; ACN53; SCH58500) consists of a replication-deficient, type 5 adenovirus vector expressing...

Malignant mesothelioma is a primary neoplasm of the mesothelial lining of the pleural (80%) or peritoneal cavities (19.5%). It has been linked conclusively to prior exposure to asbestos and may also be associated with certain genetic predispositions and past viral exposures, including SV40....