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The concept
that RNA has catalytic activity is driving the field of ribozyme technology in
a number of exciting directions. Exploiting ribozymes as a means of reducing
the levels of specific intracellular proteins offers multiple therapeutic
opportunities however identifying ways of stabilizing ribozymes must first be
identified. Field leaders at Perdue have developed a highly novel strategy for
facilitating such stabilization, thereby optimizing gene therapy. This group
has in effect mimicked a viral molecular motor that has been shown to play a
novel and essential role in packaging bacterial virus phi29 DNA into
procapsids. This motor is based on 6 strands of RNA termed packaging RNA or
pRNA. The pRNA
monomer contains two functional domains: the procapsid binding domain and the
DNA translocating domain. The procapsid binding domain is located at the
central part of the pRNA molecule, while the DNA translocation domain is
located at the 5/3 paired ends. Available data suggest that phi29 pRNA
could be a vector to escort and chaperone small therapeutic RNA molecules.
This concept has now been investigated by the Perdue group and will be
reported in a soon to be published edition of the journal Gene Therapy(1).
A chimeric pRNA/hammerhead ribozyme was designed using a ribozyme that targets
the polyA signal of the mRNA of hepatitis B virus (HBV) as a model system. The
ribozyme was designed to cleave a 137-nucleotide HBV-polyA fragment substrate
into two fragments of 70 and 67 nucleotides. This was connected to the 5
and 3 ends of pRNA. The pRNA was found to be able to chaperone and escort
the hammer-head ribozyme to function in the cell, enhancing the cleavage
efficiency and inhibition effect of the ribozyme on HBV. The mechanism for
such an increase in ribozyme activity is probably due to the fact that the
pRNA can prevent the ribozyme from misfolding and protect the ribozyme from
degradation by exonucleases present in cells. These are common reasons for the
limited therapeutic efficacy of ribozymes developed to date and hence the use
of pRNA is this fashion offers a novel way of harnessing the full potential of
ribozyme technology. This particular example offers a highly attractive
therapy for the treatment of HBV infection, however this technology could be
adapted to other ribozymes that are relevant to alternative disease states. Of particular note is the possibility of developing this technology to improve the targeting of the ribozyme. Since pRNA is a hexamer, multiple subunits can be linked to a separate therapeutic molecule. For example one subunit can be fused to the ribozyme, while another can be fused to a molecules able to bind receptors specific to the target cell. Alternatively cancer therapeutics is characterized by a multimodel approach. Thus, optimization of ribozyme technology should allow the simultaneous delivery of multiple anti-cancer therapeutics. Entry date Adapted from Shu & Guo, J Biol Chem 2003 Feb 28;278(9):7119-25 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct. (1) Hoeprich S,
Qi G, Guo S, Shu D, Wang Y and Guo P. 2003. Phi29 pRNA as a Hammerhead
Ribozyme Escort to Destroy Hepatitis B Virus, Gene Therapy (Nature Publishers)
(in press).
Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk Projects such as these are overviewed in full DiscoveryDossiers. LeadDiscovery and BioPortfolio aims to provide reliable, insightful analysis on the biotechnology industry. However, this information is provided "as is" and no representations or warranties either express or implied of completeness, accuracy, or of any other nature are made with respect to this information. This information is neither an offer to sell nor a solicitation to buy the securities of any company. This information contains forward-looking statements, which involve risks and uncertainties which may not be listed. The biotechnology industry is an emerging industry and the securities of the companies mentioned in this report have a very high degree of risk and volatility. For this reason, this information is supplied on the condition that the reader will make his or her own determination as to its suitability for any purpose prior to any use of this information. The employees and officers of LeadDiscovery and BioPortfolio may hold positions in some or all of the stocks discussed in this report. This abstract has been produced by LeadDiscovery Ltd. Founded by life scientists for life scientists we aim to help industry identify cutting edge drug discovery options and academic/biotech institutions maximize the potential of their research. Abstracts strictly reflect the opinion of LeadDiscovery's editorial panel. While all reasonable efforts are made to ensure the accuracy of information provided LeadDiscovery and the publisher BioPortfolio, takes no responsibility for incorrect or misleading information. LeadDiscovery is designed for educational and drug development purposes only and is not intended or designed to offer medical advice or advice of any sort, and must not be used for such purpose. The information provided through LeadDiscovery and BioPortfolio should not be used for diagnosing or treating a health problem or a disease and no reliance should be placed on any information contained in this abstract or elsewhere on LeadDiscovery's and BioPortfolio's website. It is not intended to be a substitute for professional care. If you have or suspect you may have a health problem, you should consult your physician or other health care provider. |
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