(researchers in Australia are using GDNF and delivering it via monoclonal antibody in rats)
Copyright © 2006 Elsevier Inc. All rights reserved.
Regular Article
GDNF gene delivery via the p75NTR receptor rescues injured motor neurons

Shahram Barati, a, , Plinio R. Hurtado1, a, Shu H. Zhanga, Rogan Tinsley2, a, Ian A. Fergusona and Robert A. Rusha

aDepartment of Human Physiology and Centre for Neuroscience, Flinders Medical Research Institute, Flinders University of South Australia, GPO Box 2100, Adelaide 5001, Australia

Received 9 January 2006; revised 19 May 2006; accepted 20 May 2006. Available online 13 July 2006.




Abstract
The retrograde axonal transport mechanism of motor neurons has been exploited to deliver the gene encoding Glial cell line-derived neurotrophic factor (GDNF) into the central nervous system to provide trophic support following injury. A nonviral gene delivery system, consisting of a monoclonal antibody (MC192) that binds the neurotrophic receptor, p75NTR, coupled to poly-L-lysine, was constructed and used to deliver the gene via a receptor-mediated mechanism. The MC192-poly-l-lysine/pGDNF complex was injected into the hind limb of newborn rats to allow gene expression within motor neurons prior to sciatic nerve transection. In adult rats, the gene delivery complex was administrated in gel foam placed on a transected hypoglossal nerve.

We show that the delivered construct is internalized following binding to p75NTR and is transported into the brain and spinal cord, bypassing the blood–brain barrier. The presence of the GDNF transgene and its transcript could be detected for up to 8 weeks in spinal cord and brain stem.

Expression of the GDNF protein rescued 38% of the targeted motor neurons 1 week postinjury in newborn rats while the survival rate in control group was below 12%. In adult rats, neuronal death induced by axotomy was almost completely reversed by the introduction of the transgene (95 ± 3%). Thus, the significant functional outcomes of this novel gene delivery system are demonstrated both in postnatal and adult motor neurons.

Keywords: Neuronal gene therapy; Neurotrophin; p75NTR; Receptor-mediated gene delivery; Nonviral



Corresponding author. Fax: +61 8 8204 5768.
1 Current address: Department of Renal Medicine, Royal Adelaide Hospital and The Hanson Institute, Adelaide 5000, Australia.
2 Current address: Howard Florey Institute, C/- University, Melbourne, Parkville, VIC 3010, Australia.

Experimental Neurology
Volume 202, Issue 1 , November 2006, Pages 179-188
(excuse lack of web address link--my address bar has disappeared and no children on premises to help recover it)