Cell penetrating peptide conjugates of steric block oligonucleotides.
Charge neutral steric block oligonucleotide analogues, such as peptide nucleic acids (PNA) or phosphorodiamidate morpholino oligomers (PMO), have promising biological and pharmacological properties for antisense applications, such as for example in mRNA splicing redirection. However, cellular uptake of free oligomers is poor and the utility of conjugates of PNA or PMO to cell penetrating peptides (CPP), such as Tat or Penetratin, is limited by endosomal sequestration. Two new families of arginine-rich CPPs named (R-Ahx-R)(4) AhxB and R(6)Pen allow efficient nuclear delivery of splice correcting PNA and PMO at micromolar concentrations in the absence of endosomolytic agents. The in vivo efficacy of (R-Ahx-R)(4) AhxB PMO conjugates has been demonstrated in mouse models of Duchenne muscular dystrophy and in various viral infections.
UMR 5235 CNRS, Université Montpellier 2, Place Eugene Bataillon, 34095 Montpellier cedex 5, France. bernard.lebleu@univ-montp2.fr
Bernard
B
Lebleu
Hong M
HM
Moulton
Rachida
R
Abes
Gabriela D
GD
Ivanova
Said
S
Abes
David A
DA
Stein
Patrick L
PL
Iversen
Andrey A
AA
Arzumanov
Michael J
MJ
Gait
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002463:Cell Membrane Permeability; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D015394:Molecular Structure; D009841:Oligonucleotides / Q000737:chemistry*; D020135:Peptide Nucleic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics
D009841:Oligonucleotides; D020135:Peptide Nucleic Acids; D010455:Peptides