Gene Therapy

J. Thomas August
Published in: Academic Press
Release Year: 2019
ISBN: 0- 12-032941-7
Pages: 527
Edition: Advance in Pharmacology
Volume 40
File Size: 29 MB
File Type: pdf
Language: English

Description of Gene Therapy

Gene Therapy Interest in developing antisense technology and in exploiting it for therapeutic purposes has become intense. Although progress has been gratifyingly rapid, the technology remains in its infancy and the questions that remain to be answered still outnumber the questions for which there are answers. Appropriately, considerable debate continues about the breadth of the utility of the approach and about the type of data required to prove that a drug works through an antisense mechanism.
The objectives of this chapter are to provide a summary of progress, to assess the status of the technology, to place the technology in the pharmacological context in which it is best understood, and to deal with some of the controversies with regard to the technology and the interpretation of experiments. Clearly, the antisense concept derives from an understanding of nucleic acid structure and function and depends on Watson-Crick hybridization (Watson and Crick, 1953). Thus, arguably, the demonstration that nucleic acid hybridization is feasible (Gillespie and Spiegelman, 1965) and the advances in in situ hybridization and diagnostic probe technology (Thompson and Gillespie, 1990) lay the most basic elements of the foundation supporting the antisense concept.

However, the first clear enunciation of the concept of exploiting antisense oligonucleotides as therapeutic agents was in the work of Zamecnik and Stephenson (1978). In their publication, these authors reported the synthesis of an oligodeoxyribo-nucleotide 13 nucleotides long that was complementary to a sequence in the Rous sarcoma virus genome. They suggested that this oligonucleotide could be stabilized by 3’- and 5’-terminal modifications and showed evidence of antiviral activity. More important, they discussed possible sites for binding in RNA and mechanisms of action of oligonucleotides.
Although less precisely focused on the therapeutic potential of antisense oligonucleotides, the work of Miller and Ts’o and their collaborators during the same period helped establish the foundation for antisense research and reestablish an interest in phosphate backbone modifications as approaches to improve the properties of oligonucleotides (Ts’o et al., 1983; Barrett et al., 1974; Miller, 1989). Their focus on ethyl phosphotriester-modified oligonucleotides as a potential medicinal chemical solution to pharmacokinetic limitations of oligonucleotides presaged much of the medicinal chemistry to be performed on oligonucleotides.
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