Design and Testing of Ribozymes for Cancer Gene Therapy

Norris, James S.; Hoel, Brian; Voeks, Dale J.; Maggouta, Frideriki; Dahm, Michael; Pan, Weihua; Clawson, Gary A.

doi:10.1007/0-306-46817-4_25

Cited by 10 publications

(3 citation statements)

References 16 publications

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“…Using our CLIP [Benedict et al, 1998;Crone et al, 1999;Ren et al, 1999;Norris et al, 2000], SNIP and SNIP AA Rz expression cassettes [Zhang et al, 2002;Pan et al, 2003, hRz targeted to library selected sites were shown to effectively block hepatitis B virus (HBV) replication within cultured HepG2 cells [Pan et al, 2001], with major decreases in HBSAg secretion, viral mRNAs, and viral DNA. We also documented efficient downregulation of human papillomavirus (HPV) type 16 and 11 E6/E7 transcripts within cultured cells [Pan et al, 2003.…”

Section: In Vitro Library Selectionmentioning

confidence: 98%

Antisense applications for biological control

Pan

Clawson

2006

J. Cell. Biochem.

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Although Nature's antisense approaches are clearly impressive, this Perspectives article focuses on the experimental uses of antisense reagents (ASRs) for control of biological processes. ASRs comprise antisense oligonucleotides (ASOs), and their catalytically active counterparts ribozymes and DNAzymes, as well as small interfering RNAs (siRNAs). ASOs and ribozymes/DNAzymes target RNA molecules on the basis of Watson-Crick base pairing in sequence-specific manner. ASOs generally result in destruction of the target RNA by RNase-H mediated mechanisms, although they may also sterically block translation, also resulting in loss of protein production. Ribozymes and DNAzymes cleave target RNAs after base pairing via their antisense flanking arms. siRNAs, which contain both sense and antisense regions from a target RNA, can mediate target RNA destruction via RNAi and the RISC, although they can also function at the transcriptional level. A considerable number of ASRs (mostly ASOs) have progressed into clinical trials, although most have relatively long histories in Phase I/II settings. Clinical trial results are surprisingly difficult to find, although few ASRs appear to have yet established efficacy in Phase III levels. Evolution of ASRs has included: (a) Modifications to ASOs to render them nuclease resistant, with analogous modifications to siRNAs being developed; and (b) Development of strategies to select optimal sites for targeting. Perhaps the biggest barrier to effective therapies with ASRs is the "Delivery Problem." Various liposomal vehicles have been used for systemic delivery with some success, and recent modifications appear to enhance systemic delivery, at least to liver. Various nanoparticle formulations are now being developed which may also enhance delivery. Going forward, topical applications of ASRs would seem to have the best chances for success. In summary, modifications to ASRs to enhance stability, improve targeting, and incremental improvements in delivery vehicles continue to make ASRs attractive as molecular therapeutics, but their advance toward the bedside has been agonizingly slow.

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Section: In Vitro Library Selectionmentioning

confidence: 98%

Antisense applications for biological control

Pan

Clawson

2006

J. Cell. Biochem.

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“…A ribozyme is a specifically structured RNA molecule with catalyzing activity (Figure 3(a)). It has been used as a potential therapy for treating cancers and infectious diseases by targeting and cleaving specific cancer or viral gene transcripts 55,56. As circular permutation approaches can replace the pRNA 5′/3′ ends with other sequences without affecting its correct folding and function,13,14 pRNA can be used as a carrier for ribozymes.…”

Section: Applications Of Prna In Drug Deliverymentioning

confidence: 99%

Current advances in Phi29 pRNA biology and its application in drug delivery

Hemida

Zhang

et al. 2012

WIREs RNA

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Bacteriophage 29 (Phi29) packaging RNA (pRNA) is one of the key components in the viral DNA-packaging motor. It contains two functional domains facilitating the translocation of DNA into the viral capsid by interacting with other elements in the motor and promoting adenosine triphosphates hydrolysis. Through the connection between interlocking loops in adjacent pRNA monomers, pRNA functions in the form of multimer ring in the motor. Previous studies have addressed the unique structure and conformation of pRNA. However, there are different DNA-packaging models proposed for the viral genome transportation mechanism. The DNA-packaging ability and the unique features of pRNA have been attracting efforts to study its potential applications in nanotechnology. The pRNA has been proved to be a promising tool for delivering nucleic acid-based therapeutic molecules by covalent linkage with ribozymes, small interfering RNAs, aptamers, and artificial microRNAs. The flexibility in constructing dimers, trimers, and hexamers enables the assembly of polyvalent nanoparticles to carry drug molecules for therapeutic purposes, cell ligands for target delivery, image detector for drug entry monitoring, and endosome disrupter for drug release. Besides these fascinating pharmacological advantages, pRNA-based drug delivery has also been demonstrated to prolong the drug half life with minimal induction of immune response and toxicity.

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“…Ribozymes are unique RNA enzymes that can recognize and cleave other RNA molecules in a sequence‐specific fashion (34). They were initially used to inhibit gene expression in HIV virus (35) and cancer (36). Compared with the antisense oligos, ribozymes offer significant advantages: (i) they operate as site‐specific ribonucleases, resulting in catalytical cleavage of the target mRNAs; (ii); they are more stringent than antisense oligos in binding mRNA targets; (iii) controls for ribozyme activity can be made by substituting nucleotides in the catalytic core to produce an inactive ribozyme (37).…”

Section: Approaches To Studying the Function Of Endogenous Rgs Proteinsmentioning

confidence: 99%

Regulators of G protein signaling (RGS proteins): Novel central nervous system drug targets

Neubig

2002

The Journal of Peptide Research

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Many drugs of abuse signal through receptors that couple to G proteins (GPCRs), so the factors that control GPCR signaling are likely to be important to the understanding of drug abuse. Contributions by the recently identified protein family, regulators of G protein signaling (RGS) to the control of GPCR function are just beginning to be understood. RGS proteins can accelerate the deactivation of G proteins by 1000-fold and in cell systems they profoundly inhibit signaling by many receptors, including mu-opioid receptors. Coupled with the known dynamic regulation of RGS protein expression and function, they are of obvious interest in understanding tolerance and dependence mechanisms. Furthermore, drugs that could inhibit their activity could be useful in preventing the development of or in treating drug dependence.

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Design and Testing of Ribozymes for Cancer Gene Therapy

Cited by 10 publications

References 16 publications

Antisense applications for biological control

Antisense applications for biological control

Current advances in Phi29 pRNA biology and its application in drug delivery

Regulators of G protein signaling (RGS proteins): Novel central nervous system drug targets

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