Adeno-associated viral vector-mediated gene transfer of brain-derived neurotrophic factor reverses atrophy of rubrospinal neurons following both acute and chronic spinal cord injury.
Rubrospinal neurons (RSNs) undergo marked atrophy after cervical axotomy. This progressive atrophy may impair the regenerative capacity of RSNs in response to repair strategies that are targeted to promote rubrospinal tract regeneration. Here, we investigated whether we could achieve long-term rescue of RSNs from lesion-induced atrophy by adeno-associated viral (AAV) vector-mediated gene transfer of brain-derived neurotrophic factor (BDNF). We show for the first time that AAV vectors can be used for the persistent transduction of highly atrophic neurons in the red nucleus (RN) for up to 18 months after injury. Furthermore, BDNF gene transfer into the RN following spinal axotomy resulted in counteraction of atrophy in both the acute and chronic stage after injury. These novel findings demonstrate that a gene therapeutic approach can be used to reverse atrophy of lesioned CNS neurons for an extended period of time.
Graduate School for Neurosciences Amsterdam, Netherlands Institute for Brain Research, Amsterdam ZO, The Netherlands.
Marc J
MJ
Ruitenberg
Bas
B
Blits
Paul A
PA
Dijkhuizen
Erik T
ET
te Beek
Arne
A
Bakker
Joop J
JJ
van Heerikhuize
Chris W
CW
Pool
Wim T J
WT
Hermens
Gerard J
GJ
Boer
Joost
J
Verhaagen
D000208:Acute Disease; D000818:Animals; D001284:Atrophy / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D019771:Axotomy; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D002908:Chronic Disease; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004525:Efferent Pathways / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics* / Q000627:therapeutic use; D008297:Male; D009416:Nerve Regeneration / Q000187:drug effects / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011930:Reaction Time / Q000235:genetics; D020813:Receptor, trkB / Q000378:metabolism; D012012:Red Nucleus / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D012183:Retrograde Degeneration / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D013116:Spinal Cord / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*
D019208:Brain-Derived Neurotrophic Factor; D020813:Receptor, trkB