Insect GDNF:TTC fusion protein improves delivery of GDNF to mouse CNS.
With a view toward improving delivery of exogenous glial cell line-derived neurotrophic factor (GDNF) to CNS motor neurons in vivo, we evaluated the bioavailability and pharmacological activity of a recombinant GDNF:tetanus toxin C-fragment fusion protein in mouse CNS. Following intramuscular injection, GDNF:TTC but not recombinant GDNF (rGDNF) produced strong GDNF immunostaining within ventral horn cells of the spinal cord. Intrathecal infusion of GDNF:TTC resulted in tissue concentrations of GDNF in lumbar spinal cord that were at least 150-fold higher than those in mice treated with rGDNF. While levels of immunoreactive choline acetyltransferase and GFRalpha-1 in lumbar cord were not altered significantly by intrathecal infusion of rGNDF, GDNF:TTC, or TTC, only rGDNF and GDNF:TTC caused significant weight loss following intracerebroventricular infusion. These studies indicate that insect cell-derived GDNF:TTC retains its bi-functional activity in mammalian CNS in vivo and improves delivery of GDNF to spinal cord following intramuscular- or intrathecal administration.
Li
Jianhong
J
Cecil B Day Laboratory for Neuromuscular Research, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Chian
Ru-Ju
RJ
Ay
Ilknur
I
Kashi
Brenda B
BB
Celia
Samuel A
SA
Tamrazian
Eric
E
Pepinsky
R Blake
RB
Fishman
Paul S
PS
Brown
Robert H
RH
Francis
Jonathan W
JW
D000818:Animals; D001682:Biological Availability; D016503:Drug Delivery Systems; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007273:Injections, Intramuscular; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013116:Spinal Cord / Q000378:metabolism*; D013744:Tetanus Toxin / Q000008:administration & dosage* / Q000493:pharmacokinetics
D051100:Glial Cell Line-Derived Neurotrophic Factor; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D013744:Tetanus Toxin; C040635:tetanus toxin fragment C