Insect GDNF: TTC fusion protein improves delivery of GDNF to mouse CNS

Cecil B Day Laboratory for Neuromuscular Research, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 10/2009; 390(3):947-51. DOI: 10.1016/j.bbrc.2009.10.083
Source: PubMed

ABSTRACT 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.

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    • "The C-terminal domain of tetanus toxin (Hc-TeTx) is used by the clostidial neurotoxin to bind to the neuronal membrane, after it is endocyted and carried through axons to arrive at the inhibitory glycinergic and GABAergic neurons of the spinal cord and brain stem. That is why the Hc-TeTx fragment has been proposed as a carrier to deliver molecules to the CNS (Payne et al., 2006; Larsen et al., 2006; Li et al., 2009; Ciriza et al., 2008). In addition, evidence suggests that the intramuscular administration of Hc-TeTx in rodents results in the delivery of the fragment to the brain. "
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