Delivery of therapeutic oligonucleotides with cell penetrating peptides.
Oligonucleotide-based drugs have received considerable attention for their capacity to modulate gene expression very specifically and as a consequence they have found applications in the treatment of many human acquired or genetic diseases. Clinical translation has been often hampered by poor biodistribution, however. Cell-penetrating peptides (CPPs) appear as a possibility to increase the cellular delivery of non-permeant biomolecules such as nucleic acids. This review focuses on CPP-delivery of several classes of oligonucleotides (ONs), namely antisense oligonucleotides, splice switching oligonucleotides (SSOs) and siRNAs. Two main strategies have been used to transport ONs with CPPs: covalent conjugation (which is more appropriate for charge-neutral ON analogues) and non-covalent complexation (which has been used for siRNA delivery essentially). Chemical synthesis, mechanisms of cellular internalization and various applications will be reviewed. A comprehensive coverage of the enormous amount of published data was not possible. Instead, emphasis has been put on strategies that have proven to be effective in animal models of important human diseases and on examples taken from the authors' own expertise.
Centre de Recherche de Biochimie Macromoléculaire, UMR 5237 CNRS, 1919 Route de Mende, 34293 Montpellier, France. Electronic address: prisca.boisguerin@crbm.cnrs.fr.
Prisca
P
Boisguérin
Centre de Recherche de Biochimie Macromoléculaire, UMR 5237 CNRS, 1919 Route de Mende, 34293 Montpellier, France.
Sébastien
S
Deshayes
Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
Michael J
MJ
Gait
Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
Liz
L
O'Donovan
University of Oxford, Department of Physiology, Anatomy and Genetics, South Parks Road, Oxford OX1 3QX, UK.
Caroline
C
Godfrey
University of Oxford, Department of Physiology, Anatomy and Genetics, South Parks Road, Oxford OX1 3QX, UK.
Corinne A
CA
Betts
University of Oxford, Department of Physiology, Anatomy and Genetics, South Parks Road, Oxford OX1 3QX, UK.
Matthew J A
MJ
Wood
UMR 5235 CNRS, Université Montpellier 2, Place Eugene Bataillon, Montpellier 34095, France.
Bernard
B
Lebleu
D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001692:Biological Transport; D002460:Cell Line; D057846:Cell-Penetrating Peptides / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D004705:Endocytosis; D006801:Humans; D008969:Molecular Sequence Data; D009136:Muscular Dystrophies / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use
D000900:Anti-Bacterial Agents; D000998:Antiviral Agents; D057846:Cell-Penetrating Peptides; D004337:Drug Carriers; D009841:Oligonucleotides
Antisense oligonucleotides; Cell penetrating peptides; Delivery; Splice switching oligonucleotides; siRNAs