Synthetic Hammerhead Ribozymes as Therapeutic Tools to Control Disease Genes

Citti, Lorenzo; Rainaldi, Giuseppe

doi:10.2174/1566523052997541

Cited by 77 publications

(51 citation statements)

References 124 publications

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“…(1) Ribozymes: 2,3 These were discovered in the 1970s, and the elucidation of the transactivating hammerhead ribozyme later led to their study for therapeutic applications including viral infections and cancer. In addition to possessing catalytic activities as well as binding capacity to the RNA, the hammerhead ribozymes can cause RNase-dependent degradation of the target double-stranded RNA (dsRNA).…”

Section: Genomic-based Strategiesmentioning

confidence: 99%

siRNA-based approaches in cancer therapy

2006

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The availability of the human genome sequence has revolutionized the strategy of employing nucleic acids with sequences complementary to specific target genes to improve drug discovery and target validation. Development of sequence-specific DNA or RNA analogs that can block the activity of selected single-stranded genetic sequences offers the possibility of rational design with high specificity, lacking in many current drug treatments for various diseases including cancer, at relatively inexpensive costs. Antisense technology is one such example that has shown promising results and boasts of yielding the only approved drug to date in the genomics field. However, in vivo delivery issues have yet to be completely overcome for widespread clinical applications. In contrast to antisense oligonucleotides, the mechanism of silencing an endogenous gene by the introduction of a homologous double-stranded RNA (dsRNA), transgene or virus is called post-transcriptional gene silencing (PTGS) or RNA interference. PTGS is a natural mechanism whereby metazoan cells suppress expansion of genes when they come across dsRNA molecules with the same sequence. Short interfering RNA is currently the fastest growing sector of this antigene field for target validation and therapeutic applications. Although, in theory, the development of genomics-based agents to inhibit gene expression is simple and straightforward, the fundamental concern relies upon the capacity of the oligonucleotide to gain access to the target RNA. This paper summarizes the advances in the last decade in the field of PTGS using RNA interference approaches and provides relevant comparisons with other oligonucleotide-based approaches with a specific focus on oncology applications. Cancer Gene Therapy (2006) Genomic-based strategiesThe American Cancer Society estimates that, in 2005, a total of 1 372 910 new cancer cases and 570 280 deaths are expected in the United States. 1 These morbid statistics demonstrate the necessity of newer therapeutic modalities for achieving successful cancer treatment and cure. Downregulation of genes that contribute to cancer progression has been the goal of targeted genomics-based strategies, with the expectation that such an approach may lead to selective and specific inhibition of tumor growth with minimal untoward side effects on normal cells. Identification of target genes involved in neoplastic transformation and tumor progression has triggered the idea that nucleotide sequences of cancer-relevant genes could lead to the development of tailored anticancer agents that lack many of the toxic side effects of traditional cytotoxic drugs. This has led to a recent acceleration in the development and optimization of genomic-based strategies for cancer therapy. This idea dates back to the 1960s when RNA sequences were shown to serve as endogenous inhibitors of gene expression in procaryotes. The antigene approaches include the following:(1) Ribozymes: 2,3 These were discovered in the 1970s, and the elucidation of the transactivating hammerh...

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Section: Genomic-based Strategiesmentioning

confidence: 99%

siRNA-based approaches in cancer therapy

2006

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“…Because of its small size and high nuclease activity, this ribozyme is an attractive candidate for therapeutic and diagnostic uses [2]. HH(S) and HH(L) investigated in this study are hammerhead ribozymes having different number of base pairs formed with the substrate RNA ( Figure 1a).…”

Section: Substrate Cleavage By Ribozymesmentioning

confidence: 99%

“…Several types of nucleic acid enzymes have been found in living cells or were artificially made through in vitro selection using libraries of random sequence [1]. Specifically, the hammerhead ribozyme and the 8-17 DNAzyme, which effectively catalyze the site-specific cleavage of the phosphodiester bond of an RNA substrate, have been used as inhibitors of intracellular gene expression [2,3] and as biosensors for detecting target metal ions, molecules, or specific DNA and RNA sequences [4][5][6][7][8][9]. The flexibility in nucleic acid sequence design enables to convert these enzymes into ligand-responsive aptazyme systems regulating gene expression levels and into sensitive electrochemical sensors [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Catalytic Activities of Ribozymes and DNAzymes in Water and Mixed Aqueous Media

2017

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Catalytic nucleic acids are regarded as potential therapeutic agents and biosensors. The catalytic activities of nucleic acid enzymes are usually investigated in dilute aqueous solutions, although the physical properties of the reaction environment inside living cells and that in the area proximal to the surface of biosensors in which they operate are quite different from those of pure water. The effect of the molecular environment is also an important focus of research aimed at improving and expanding nucleic acid function by addition of organic solvents to aqueous solutions. In this study, the catalytic activities of RNA and DNA enzymes (hammerhead ribozyme, 17E DNAzyme, R3C ribozyme, and 9DB1 DNAzyme) were investigated using 21 different mixed aqueous solutions comprising organic compounds. Kinetic measurements indicated that these enzymes can display enhanced catalytic activity in mixed solutions with respect to the solution containing no organic additives. Correlation analyses revealed that the turnover rate of the reaction catalyzed by hammerhead ribozyme increased in a medium with a lower dielectric constant than water, and the turnover rate of the reaction catalyzed by 17E DNAzyme increased in conditions that increased the strength of DNA interactions. On the other hand, R3C ribozyme and 9DB1 DNAzyme displayed no significant turnover activity, but their single-turnover rates increased in many mixed solutions. Our data provide insight into the activity of catalytic nucleic acids under various conditions that are applicable to the medical and technology fields, such as in living cells and in biosensors.

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“…Since then, gene-tailored ribozymes have been designed, produced and given to cells to 'knock down' the expression of specific genes. 69 In this regard, adenovirus-mediated ribozyme targeting of HER-2/neu inhibited in vivo growth of breast cancer cells in a mouse model. 70 Further, ribozyme-mediated cleavage of the human survivin mRNA and inhibition of antiapoptotic function of survivin in MCF-7 cells could be demonstrated.…”

Section: Mutation Compensationmentioning

confidence: 99%