Important note: Information in this article was accurate in 1993. The state of the art may have changed since the publication date.
Ribozymes as potential therapeutic agents (Meeting abstract).
Proc Annu Meet Am Assoc Cancer Res; 34:592-3 1993. Unique Identifier : AIDSLINE MED/93694341 Rossi JJ; Bertrand E; Larson G; Kohn D; Zhou C; Wu Y; Snyder D; Beckman Res. Inst. of the City of Hope, Duarte, CA 91010
Abstract:
The uses of nucleic acids as antisense or therapeutic agents have been expanding rapidly due, in large part, to improvements in the automated chemical synthesis of DNA and, more recently, RNA. As therapeutic agents, antisense DNA and RNA have the singular property of being 'informational' drugs with unique target specificity, making them potentially less toxic than other drugs. The discovery that RNA, apart from being an informational molecule, also has potential for being a catalytic molecule led to development of catalytic, antisense RNAs--ribozymes--that can pair with and cleave any chosen target RNA. The simplest catalytic domain found in RNA is derived from the self-cleaving structure of plant viroids and virusoids and has been termed the hammerhead.' We took advantage of the simplicity of this catalytic domain to develop hammerhead-type ribozymes as therapeutic agents for the treatment of both viral disease and certain cancers. The unique properties of retroviral infection make them attractive targets for drug development. Because ribozymes can be targeted to virtually any sequence of interest, they offer great potential as therapeutic agents in the treatment of HIV-1 infection, and can be used to circumvent the problem of viral resistance by choosing targets in highly conserved regions or by using multiple targets simultaneously. We have developed a number of different ribozymes to various regions of the HIV-1 and SIV-1 genomes. By incorporating ribozymes into amphotropic retroviral vectors, we successfully transfected human T lymphocytes with ribozymes targeted to HIV-1-encoded tat, rev and gag. These retrovirally transfected cells are resistant to HIV-1 infection. The transfection of bone marrow cells with similar retroviral constructs is now in progress. The successful transfection of these cells will facilitate the clinical application of ribozymes for the treatment of HIV-1 infection via autologous bone marrow transplantation. To enhance the targeting efficiency of ribozymes, we developed novel targeting strategies, which are discussed. We have recently developed a novel DNA-RNA chimeric ribozyme for use as an exogenously administered therapeutic reagent. In these molecules, DNA is substituted for RNA in the base-pairing regions, while RNA remains in the catalytic center. Advantages of these molecules over all RNA ribozymes are enhanced intracellular stability and higher catalytic turnover. We have used these ribozymes to test the possibility of cleaving bcr-abl fusion transcripts as a possible means of ex vivo purging of bone marrow in CML. We showed that these chimeric ribozymes effectively cleave the bcr-abl transcript, substantially reducing the amount of p-210 fusion protein and inhibiting the growth of EM2 cells in culture. When compared to a ribozyme with a point mutation in the catalytic center, the active ribozyme has significantly more inhibitory activity, strongly suggesting cleavage of the bcr-abl message. The results of our studies, as well as those of others, lend strong support to the contention that ribozymes can be effective as both antiviral and anticancer therapeutic agents. (5 Refs)
Keywords: *DNA, Antisense *RNA, Antisense *RNA, Catalytic/THERAPEUTIC USE 931130
M93B5834
AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Important note: Information in this article was accurate in 1993. The state of the art may have changed since the publication date.
