This research is designed to expand upon the major discovery in our laboratory that systemic administration of antisense treatments utilizing peptide nucleic acids (PNAs) can be used to target and shut down proteins, including those within the brain. We have direct evidence that PNAs pass the blood brain barrier and enter neurons, where they specifically inhibit the synthesis of proteins. This discovery has the potential of lead to the development to the development of drugs that could treat a multitude of diseases. We have chosen for this proposal two proteins in rat brain, namely, the neurotensin receptor subtype 1 (NTR1) and the dopamine transporter (DAT). Thus far,, we have successfully inhibited protein production with antisense PNAs given intraperitoneally and orally to the NTR1. Accordingly, the Specific Aims of this proposal which have an overall goal of characterizing the distribution kinetics and effective of different PNAs using laboratory rats, are as follows: 1. Determine the pharmacokinetics of the NTR1 PNA in plasma and organ distribution of the PNA after administration by intravenous (iv) and oral routes. This will allow the bioavailability of NTR1 PNA by the oral route to be determined. 2. Examine the effectiveness and specificity of antisense PNAs by """"""""walking"""""""" the NTR1 message and determining the specificity of the PNAs by introducing mismatches into the PNA sequences. Examine the effectiveness of a PNA directed at the DAT for changes in motility behavior, protein levels, and mRNA. In addition, determine the onset and offset kinetics of this PNA as well as with dose response data.
| McMahon, Beth M; Stewart, Jennifer A; Bitner, M D et al. (2002) Peptide nucleic acids specifically cause antigene effects in vivo by systemic injection. Life Sci 71:325-37 |
| McMahon, B M; Stewart, J A; Jackson, J et al. (2001) Intraperitoneal injection of antisense peptide nucleic acids targeted to the mu receptor decreases response to morphine and receptor protein levels in rat brain. Brain Res 904:345-9 |
| Tyler-McMahon, B M; Stewart, J A; Jackson, J et al. (2001) Altering behavioral responses and dopamine transporter protein with antisense peptide nucleic acids. Biochem Pharmacol 62:929-32 |
