Ribozyme therapy

CHRONIC MYELOGENOUS LEUKEMIA (CML) AND THE POTENTIAL FOR RIBOZYME THERAPY... 

Antisense Oligonucleotides. Table 1 Malignant disorders as potential targets for ribozyme gene therapy... 

Kleimnan et al. 2008). In addition, synthetic siRNAs are also subject to degradation in vivo by nuclease activity. Besides side effects and instability, the efficient and specific delivery of the RNAi indncers to the target cell still requires optimization. Here we snmmarize the cnrrent statns of nncleic acid-based antiviral therapentics. The focns will be on antiviral strategies nsing antisense and RNAi technology. Additionally, antiviral ribozymes and aptamers will be discussed briefly, with a focus on recent studies. Gene therapy approaches and delivery systems are the subject of Chapter 11 of this book. 

The development of nucleic acid-based therapeutics is not as straightforward as researchers had initially anticipated. Stability, toxicity, specificity, and delivery of the compounds continue to be challenging issues that need further optimization. In recent years, researchers have come up with intricate solutions that have greatly improved the efficacy of potential antisense, ribozyme, as well as RNAi-based therapeutics. Clinical trials for all these types of nucleic acid-based therapeutics are underway. So far, data from several trials and studies in animal models look promising, in particular, the therapies that trigger the RNAi pathway. However, history has shown that compounds that do well in phase I or phase II clinical trials may still fail in phase III. A striking example is the nonspecific suppression of angiogenesis by siRNA via toII-Iike receptor 3 (Kleinman et al. 2008). It will become clear in the near future which compounds will make it as a new class of antiviral therapeutics. 

Antisense RNAs, RNA decoys, ribozymes, small interfering RNAs, and RNA ap-tamers are potential tools in antiviral gene therapy. The application of the antiviral RNAs is described in detail in Chap. 9 of this volnme by J. Haasnoot and B. Berkhont. 

Bai J, Rossi J, Akkina R (2001) Multivalent anti-CCR ribozymes for stem cell-based HIV type 1 gene therapy. AIDS Res Hum Retroviruses 17 385-399 Bai J, Sui J, Zhu RY, TaUarico AS, Gennari F, Zhang D, Marasco WA (2003) Inhibition of Tat-mediated transactivation and HIV-1 replication by human anti-hCychnTl intrabodies. J Biol Chem 278 1433-1442... 

Lewin, A. and Hauswirth, W. 2001. Ribozyme gene therapy applications for molecular medicine. Trends in Molecular Medicine 7(5), 221-228. 

Alvarez-Salas, L.M., Benitez-Hess, M.L., and DiPaolo, J.A. 2003. Advances in the development of ribozymes and antisense oligodeoxynucleotides as antiviral agents for human papillomaviruses. Antiviral Therapy 8(4), 265-278. 

Kashani-Sabet, M. 2004. Non-viral delivery of ribozymes for cancer gene therapy. Expert Opinion on Biological Therapy 4(11), 1749-1755. 

For gain-of-function mutations gene-blocking therapy, using antisense oligonucleotides or ribozymes to block gene expression... 

Lewin, A. S., and W. W. Hauswirth. Ribozyme Gene Therapy Applications for Molecular Medicine. Trends in Molecular Medicine 1 no. 5 (2001) 221-228. 

The contraindications to and tolerance of interferon-based therapies in the treatment of HCV infection are similar to those described for patients with HBV infection. As for HBV infection, considerable efforts are being made to develop new agents to improve response rates in patients with HCV infection. Direct antiviral strategies with antisense oligonucleotides, ribozymes, and inhibitors of the viral enzymes— polymerase, helicase, and protease—are under investigation. However, it is likely that interferons will continue to serve as the foundation of therapy for HCV infections, with new agents serving as adjuncts. 

Li M, Li H, Rossi JJ. 2006. RNAi in combination with ribozyme and TAR decoy for treatment of HIV infection in hematopoietic cell gene therapy. Ann NY Acad Sci. 1082 172-179. 

Feng, Y., Leavitt, M., Tritz, R., Duarte, E., Kang, D., Mamounas, M. etal. (2000) Inhibition of CCR5-dependentHFV-l infection by hairpin ribozyme gene therapy against CC-chemokine receptor 5. Virology, 276, 271-278. 

Hauswirth, W.W. and Lewin, A.S. (2000) Ribozyme uses in retinal gene therapy. Prog. Retin. Eye Res., 19, 689-710. 

LaVail, M.M., Yasumura, D., Matthes, M.T., Drenser, K.A., Flannery, J.G., Lewin, A.S. and Hauswirth, W.W. (2000) Ribozyme rescue of photoreceptor cells in P23H transgenic rats long-term survival and late-stage therapy. Proc. Natl. Acad. Sci. USA, 97, 11488-11493. 

Welch, P.J., Yei, S. and Barber, J.R. (1998) Ribozyme gene therapy for hepatitis C virus infection. Clin. Diagn. Virol, 10, 163-171. 

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