Medicinal chemistry of plasmid DNA with peptide nucleic acids: A new strategy for gene therapy |
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Authors: | Olivier Zelphati Jiin Felgner Yan Wang Xiaowu Liang Xiaodong Wang Philip Felgner |
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Institution: | (1) Gene Therapy Systems Inc., 10190 Telesis Court, 92122 San Diego, CA, USA |
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Abstract: | Summary In this chapter, we describe an approach using a peptide nucleic acid (PNA) clamp to directly and irreversibly modify plasmid
DNA, without affecting either its supercoiled conformation or its ability to be efficiently transcribed. This strategy enables
investigators to 'functionalize' their gene of interest by direct coupling of ligands (fluorophores, peptide, proteins, sugars
or oligonucleotides) to plasmid DNA. This approach provides versatile tools to study the mechanisms of gene delivery and to
circumvent some of the main obstacles of synthetic gene delivery systems, such as specific targeting and efficient delivery.
The proof-of-principal of PNA-dependent gene chemistry (PDGC) was demonstrated with a fluorescently labeled PNA that allowed
generation of a highly fluorescent preparation of plasmid DNA that was functionally and conformationally intact. Fluorescent-PNA/DNA
was used to identify critical parameters involved in naked DNA and non-viral gene delivery technology. The greatest potential
of PDGC lies in the ability to attach specific ligands (e.g., peptides, proteins) to the plasmid DNA in order to overcome
cellular barriers of non-viral gene delivery systems. In this regard, specific examples of ligands coupled to DNA are described
and their effect on increasing the efficacy of gene therapy is presented. |
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