Gene therapy: The first two decades and the current state‐of‐the‐art

Abstract

The concept of gene therapy was envisioned soon after the emergence of restriction endonucleases and subcloning of mammalian genes in phage and plasmids. Over the ensuing decades, vectors were developed, including nonviral methods, integrating virus vectors (gammaretrovirus and lentivirus), and non-integrating virus vectors (adenovirus, adeno-associated virus, and herpes simplex virus vectors). Preclinical data demonstrated potential efficacy in a broad range of animal models of human diseases, but clinical efficacy in humans remained elusive in most cases, even after decades of experience in over 1000 trials. Adverse effects from gene therapy have been observed in some cases, often because of viral vectors retaining some of the pathogenic potential of the viruses upon which they are based. Later generation vectors have been developed in which the safety and/or the efficiency of gene transfer has been improved. Most recently this work has involved alterations of vector envelope or capsid proteins either by insertion of ligands to target specific receptors or by directed evolution. The disease targets for gene therapy are multiple, but the most promising data have come from monogenic disorders. As the number of potential targets for gene therapy continues to increase, and a substantial number of trials continue with both the standard and the later generation vector systems, it is hoped that a therapeutic niche for gene therapy will emerge in the coming decades.

Causes and consequences of the evolution of reproductive proteins

“…For example, the effects of amino acid changes at positively selected sites could be tested using site-directed mutagenesis and in vitro binding assays (e.g., Kinloch et al, 1995;Chen et al, 1998;Hickox et al, 2001;Williams et al, 2003Williams et al, , 2006. Alternatively, manipulation of genes could be performed in vivo using transgenics or targeted gene transfer (Flotte, 2007;Gao et al, 2007;Waehler et al, 2007).…”

High-Throughput Sequencing Reveals Principles of Adeno-Associated Virus Serotype 2 Integration

“…Adeno-associated virus serotype 2, a nonenveloped single-stranded DNA virus, has long been considered unique among known mammalian viruses due to its capacity to integrate site-preferentially (2). AAV has also been highly successful in nonintegrating gene therapy applications (3,4). In addition to its success as a vector, the AAV integration machinery has been actively investigated for targeted integration strategies (5-7).…”

Anti-angiogenesis effect of generation 4 polyamidoamine/vascular endothelial growth factor antisense oligodeoxynucleotide on breast cancer in vitro

“…Therefore, the gene therapy, showing a great hope, gradually becomes one of the most prospective methods in biologic treatment of tumor (Edelstein et al, 2007). It is the fifth treatment modality after surgery, radiotherapy, chemotherapy, and immunotherapy (Flotte, 2007). It transfects the external functional gene or other germ plasm into the patient's body by certain ways so that it could decrease and/or increase expressions of certain genes to compensate the clinical symptom caused by the defected gene.…”