(R-Ahx-R)4 cell-penetrating peptide enhances the in vivo delivery of antisense morpholino oligomers

BIOT 184

Hong M. Moulton, moulton@avibio.com1, Natee Jearawiriyapaisarn2, Sue Fletcher3, Benjamin W Neuman4, Ryszard Kole, kole@med.unc.edu5, Wilton Steve3, Michael Buchmeier4, and Patrick L. Iversen, piversen@avibio.com1. (1) Biology, AVI BioPharma Inc, 4575 SW Research Way Suite 200, Corvallis, OR 97333, (2) University of North Carolina, Chapel Hill, NC 27599, (3) University of Western Australia, Nedlands, Australia, (4) The Scripps Research Institute, La Jolla, CA, (5) Lineberger Comprehensive Cancer Center and Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599
Morpholino oligomers (PMO) are uncharged steric-blocking antisense compounds that interfere with protein translation, pre-mRNA splicing and viral RNA synthesis. An arginine-rich cell penetrating peptide (CPP), (R-Ahx-R)4, enhances the nuclear/cytosolic delivery of PMO and has generated exciting reports in the Duchenne muscular dystrophy (DMD) and antiviral fields. Several highlights of our findings with the (R-Ahx-R)4 PMO conjugates will be presented including 1) the functional biodistribution in a splice-correction mouse model, 2) altering pre-mRNA splicing in a DMD model and 3) inhibiting the replication of coronavirus in mice. We attribute the success of this CPP to its greater ability to escape entrapment and its better enzymatic stability compared to Tat or polyarginine CPPs. Further optimization of the CPP sequence may reduce its endosomal trapping and toxicity. These studies show that, if dosed appropriately, this CPP has broad applications for delivery of therapeutic PMO.
 

Biophysical and Biomolecular Symposium: Targeted Delivery of Proteins & Nucleotides
8:00 AM-11:00 AM, Wednesday, August 22, 2007 BCEC -- 107 A/B, Oral

Division of Biochemical Technology

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007