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Medicinal Chemistry of Plasmid DNA with Peptide Nucleic Acids

A New Strategy for Gene Therapy

  • Chapter
Peptide Nucleic Acids, Morpholinos and Related Antisense Biomolecules

Part of the book series: Medical Intelligence Unit ((MIUN))

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Abstract

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-principle 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 nonviral gene delivery tech-nology. The greatest potential of PDGC lies in the ability to attach specific ligands (e.g., pep-tides, proteins) to the plasmid DNA in order to overcome cellular barriers of nonviral 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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Authors and Affiliations

  1. Center for Virus Research, University of California, Irvine, Irvine, California, USA

    Olivier Zelphati & Philip Felgner

  2. Gene Therapy Systems Inc., San Diego, California, USA

    Jiin Felgner, Yan Wang, Xiaowu Liang & Xiaodong Wang

Authors
  1. Olivier Zelphati
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  2. Jiin Felgner
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  3. Yan Wang
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  4. Xiaowu Liang
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  5. Xiaodong Wang
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  6. Philip Felgner
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Zelphati, O., Felgner, J., Wang, Y., Liang, X., Wang, X., Felgner, P. (2006). Medicinal Chemistry of Plasmid DNA with Peptide Nucleic Acids. In: Peptide Nucleic Acids, Morpholinos and Related Antisense Biomolecules. Medical Intelligence Unit. Springer, Boston, MA. https://doi.org/10.1007/0-387-32956-0_12

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