Antisense RNA gene therapy for studying and modulating biological processes.
Agents that produce their effects through an antisense mechanism offer the possibility of developing highly specific alternatives to traditional pharmacological antagonists, thereby providing a novel class of therapeutic agents, ones which act at the level of gene expression. Among the antisense compounds, antisense RNA produced intracellularly by an expression vector has been used extensively in the past several years. This review considers the advantages of the antisense RNA approach over the use of antisense oligodeoxynucleotides, the different means by which one may deliver and produce antisense RNA inside cells, and the experimental criteria one should use to ascertain whether the antisense RNA is acting through a true antisense mechanism. Its major emphasis is on exploring the potential therapeutic use of antisense RNA in several areas of medicine. For example, in the field of oncology antisense RNA has been used to inhibit several different target proteins, such as growth factors, growth factor receptors, proteins responsible for the invasive potential of tumor cells and proteins directly involved in cell cycle progression. In particular, a detailed discussion is presented on the possibility of selectively inhibiting the growth of tumor cells by using antisense RNA expression vectors directed to the individual calmodulin transcripts. Detailed consideration is also provided on the development and potential therapeutic applications of antisense RNA vectors targeted to the D2 dopamine receptor subtype. Studies are also summarized in which antisense RNA has been used to develop more effective therapies for infections with certain viruses such as the human immunodeficiency virus and the virus of hepatitis B, and data are reviewed suggesting new approaches to reduce elevated blood pressure using antisense RNA directed to proteins and receptors from the renin-angiotensin system. Finally, we outline some of the problems which the studies so far have yielded and some outstanding questions which remain to be answered in order to develop further antisense RNA vectors as therapeutic agents.
Weiss
B
B
Department of Pharmacology, MCP Hahnemann University, Philadelphia, Pennsylvania 19129, USA. weissb@auhs.edu
Davidkova
G
G
Zhou
L W
LW
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000235:genetics; D016373:DNA, Antisense / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D005786:Gene Expression Regulation / Q000187:drug effects*; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D015658:HIV Infections / Q000628:therapy; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D009369:Neoplasms / Q000628:therapy; D016716:PC12 Cells / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects*; D016372:RNA, Antisense / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000235:genetics; D012084:Renin-Angiotensin System / Q000187:drug effects; D012559:Schizophrenia / Q000628:therapy
D000959:Antihypertensive Agents; D014150:Antipsychotic Agents; D000998:Antiviral Agents; D002147:Calmodulin; D016373:DNA, Antisense; D065127:Dopamine D2 Receptor Antagonists; D009363:Neoplasm Proteins; D016372:RNA, Antisense; D017448:Receptors, Dopamine D2