Mark's buddymapping program is now up and running so please take a moment to post from your location ( see guestbook section). Mark is a Curious George when it comes to so many things in life, his recent obsession being geography. My brother Joe ( see new family photo) recently returned to his home, in Vietnam. Mark ran to the world map hanging on our wall and yelled, "Let's see where Uncle Joe and Aunt Theresa live." And, his Aunt Cheryl and cousins Tony and Chris recently returned from a trip to Australia. Mr. Inquisitive wanted to learn where this continent was located, also. I appreciate you taking the time to do this. Functionalized PEG-PEI Copolymers Complexed to Exon-Skipping Oligonucleotides Improve Dystrophin Expression in mdx Mice.
http://www.ncbi.nlm.nih.gov/pubmed/18647087
Sirsi SR, Schray RC, Guan X, Williams JH, Erney ML, Lutz GJ.
School of Biomedical Engineering, Drexel University, Philadelphia, PA 19104.
2008 Jul 22.
Exon-skipping oligonucleotides (ESOs) with 2'-O-methyl modifications are promising compounds for the treatment of Duchenne muscular dystrophy (DMD). However, the usefulness of these compounds is limited by their poor delivery profile to muscle tissue in vivo. We previously established that copolymers made of poly(ethylene imine) (PEI) and poly(ethylene glycol) (PEG) enhanced ESO transfection in skeletal muscle of mdx mice, resulting in widespread distribution of dystrophin-positive fibers, but limited dystrophin expression by Western blo t. In an attempt to improve ESO delivery and dystrophin expression, a new formulation of PEG-PEI copolymer was used, along with functionalized derivatives containing either the cell-penetrating peptide TAT (trans-activator of transcription), adsorbed colloidal gold (CG), or both TAT and CG. Tibialis anterior muscles were given three intramuscular injections of various PEG-PEI-ESO polyplexes (3 days apart; 5 mug of ESO per injection) and muscles were harvested 3 weeks after the first injection. Surface modifications of PEG-PEI copolymers with TAT showed the highest level of dystrophin recovery, with a 6-fold increase in dystrophin-positive fibers compared with ESO alone and up to 30% of normal dystrophin expression by Western blot. The adsorption of CG to either PEG-PEI or TAT-PEG-PEI copolymers showed no further improvement in dystrophin expression. Our data indicate that TAT-modified PEG-PEI copolymers are effective carriers for delivery of ESOs to skeletal muscle and are p romising compounds for the therapeutic treatment of DMD.
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