Neuroregenerative effects of lentiviral vector-mediated GDNF expression in reimplanted ventral roots.
Traumatic avulsion of spinal nerve roots causes complete paralysis of the affected limb. Reimplantation of avulsed roots results in only limited functional recovery in humans, specifically of distal targets. Therefore, root avulsion causes serious and permanent disability. Here, we show in a rat model that lentiviral vector-mediated overexpression of glial cell line-derived neurotrophic factor (GDNF) in reimplanted nerve roots completely prevents motoneuron atrophy after ventral root avulsion and stimulates regeneration of axons into reimplanted roots. However, over the course of 16 weeks neuroma-like structures are formed in the reimplanted roots, and regenerating axons are trapped at sites with high levels of GDNF expression. A high local concentration of GDNF therefore impairs long distance regeneration. These observations show the feasibility of combining neurosurgical repair of avulsed roots with gene-therapeutic approaches. Our data also point to the importance of developing viral vectors that allow regulated expression of neurotrophic factors.
Eggers
Ruben
R
Laboratory for Neuroregeneration, Netherlands Institute for Neuroscience, Institute of the Royal Academy of Arts and Sciences, Amsterdam, The Netherlands.
Hendriks
William T J
WT
Tannemaat
Martijn R
MR
van Heerikhuize
Joop J
JJ
Pool
Chris W
CW
Carlstedt
Thomas P
TP
Zaldumbide
Arnaud
A
Hoeben
Rob C
RC
Boer
Gerard J
GJ
Verhaagen
Joost
J
D000818:Animals; D001284:Atrophy / Q000517:prevention & control; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009416:Nerve Regeneration / Q000502:physiology*; D011843:Radiculopathy / Q000473:pathology / Q000601:surgery*; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism; D013126:Spinal Nerve Roots / Q000502:physiology / Q000601:surgery; D019076:Transgenes
D019208:Brain-Derived Neurotrophic Factor; D017077:Culture Media, Conditioned; D051100:Glial Cell Line-Derived Neurotrophic Factor