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

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 GFR{alpha}-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.

Authors:
; ; ; ; ;  [1];  [2];  [3];  [1]
  1. Cecil B. Day Laboratory for Neuromuscular Research, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129 (United States)
  2. BiogenIdec, Inc., 14 Cambridge Center, Cambridge, MA 02142 (United States)
  3. Research Service, Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201 (United States)
Publication Date:
OSTI Identifier:
22199923
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 390; Journal Issue: 3; Other Information: Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANIMAL TISSUES; CHOLINE; CONCENTRATION RATIO; IN VIVO; INFUSION; INSECTS; INTRAMUSCULAR INJECTION; MICE; NERVE CELLS; PROTEINS; SPINAL CORD; TETANUS; TOXINS

Citation Formats

Li, Jianhong, Chian, Ru-Ju, Ay, Ilknur, Kashi, Brenda B., Celia, Samuel A., Tamrazian, Eric, Pepinsky, R. Blake, Fishman, Paul S., Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, Brown, Robert H., and Francis, Jonathan W., E-mail: jwfrancisby@gmail.com. Insect GDNF:TTC fusion protein improves delivery of GDNF to mouse CNS. United States: N. p., 2009. Web. doi:10.1016/J.BBRC.2009.10.083.
Li, Jianhong, Chian, Ru-Ju, Ay, Ilknur, Kashi, Brenda B., Celia, Samuel A., Tamrazian, Eric, Pepinsky, R. Blake, Fishman, Paul S., Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, Brown, Robert H., & Francis, Jonathan W., E-mail: jwfrancisby@gmail.com. Insect GDNF:TTC fusion protein improves delivery of GDNF to mouse CNS. United States. https://doi.org/10.1016/J.BBRC.2009.10.083
Li, Jianhong, Chian, Ru-Ju, Ay, Ilknur, Kashi, Brenda B., Celia, Samuel A., Tamrazian, Eric, Pepinsky, R. Blake, Fishman, Paul S., Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, Brown, Robert H., and Francis, Jonathan W., E-mail: jwfrancisby@gmail.com. 2009. "Insect GDNF:TTC fusion protein improves delivery of GDNF to mouse CNS". United States. https://doi.org/10.1016/J.BBRC.2009.10.083.
@article{osti_22199923,
title = {Insect GDNF:TTC fusion protein improves delivery of GDNF to mouse CNS},
author = {Li, Jianhong and Chian, Ru-Ju and Ay, Ilknur and Kashi, Brenda B. and Celia, Samuel A. and Tamrazian, Eric and Pepinsky, R. Blake and Fishman, Paul S. and Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201 and Brown, Robert H. and Francis, Jonathan W., E-mail: jwfrancisby@gmail.com},
abstractNote = {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 GFR{alpha}-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.},
doi = {10.1016/J.BBRC.2009.10.083},
url = {https://www.osti.gov/biblio/22199923}, journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 3,
volume = 390,
place = {United States},
year = {Fri Dec 18 00:00:00 EST 2009},
month = {Fri Dec 18 00:00:00 EST 2009}
}