Adeno-associated viral vector-mediated neurotrophin gene transfer in the injured adult rat spinal cord improves hind-limb function

TY - JOUR

T1 - Adeno-associated viral vector-mediated neurotrophin gene transfer in the injured adult rat spinal cord improves hind-limb function

AU - Blits, B

AU - Oudega, M.

AU - Boer, G J

AU - Bartlett Bunge, M

AU - Verhaagen, J

PY - 2003

Y1 - 2003

N2 - To foster axonal growth from a Schwann cell bridge into the caudal spinal cord, spinal cells caudal to the implant were transduced with adeno-associated viral (AAV) vectors encoding for brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (AAV-NT-3). Control rats received AAV vectors encoding for green fluorescent protein or saline. AAV-BDNF- and AAV-NT-3-transduced 293 human kidney cells produced and secreted BDNF or NT-3, respectively, in vitro. The secreted neurotrophins were biologically active; they both promoted outgrowth of sensory neurites in vitro. In vivo, transgene expression was observed predominantly in neurons for at least 16 weeks after injection. Compared with controls, a modest though significant improvement in hind-limb function was found in rats that received AAV-BDNF and AAV-NT-3. Retrograde tracing demonstrated that twice as many neurons with processes extending toward the Schwann cell graft were present in the second lumbar cord segment of AAV-BDNF- and AAV-NT-3-injected animals compared with controls. We found no evidence, however, for growth of regenerated axons from the Schwann cell implant into the caudal cord. Our results suggest that AAV vector-mediated overexpression of BDNF and NT-3 in the cord caudal to a Schwann cell bridge modified the local lumbar axonal circuitry, which was beneficial for locomotor function.

AB - To foster axonal growth from a Schwann cell bridge into the caudal spinal cord, spinal cells caudal to the implant were transduced with adeno-associated viral (AAV) vectors encoding for brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (AAV-NT-3). Control rats received AAV vectors encoding for green fluorescent protein or saline. AAV-BDNF- and AAV-NT-3-transduced 293 human kidney cells produced and secreted BDNF or NT-3, respectively, in vitro. The secreted neurotrophins were biologically active; they both promoted outgrowth of sensory neurites in vitro. In vivo, transgene expression was observed predominantly in neurons for at least 16 weeks after injection. Compared with controls, a modest though significant improvement in hind-limb function was found in rats that received AAV-BDNF and AAV-NT-3. Retrograde tracing demonstrated that twice as many neurons with processes extending toward the Schwann cell graft were present in the second lumbar cord segment of AAV-BDNF- and AAV-NT-3-injected animals compared with controls. We found no evidence, however, for growth of regenerated axons from the Schwann cell implant into the caudal cord. Our results suggest that AAV vector-mediated overexpression of BDNF and NT-3 in the cord caudal to a Schwann cell bridge modified the local lumbar axonal circuitry, which was beneficial for locomotor function.

KW - Adenoviridae

KW - Animals

KW - Brain Tissue Transplantation

KW - Brain-Derived Neurotrophic Factor

KW - Female

KW - Fluorescent Dyes

KW - Gene Transfer Techniques

KW - Genetic Vectors

KW - Graft Survival

KW - Growth Cones

KW - Hindlimb

KW - Nerve Growth Factors

KW - Nerve Regeneration

KW - Neural Pathways

KW - Neurotrophin 3

KW - Rats

KW - Rats, Inbred F344

KW - Recombinant Fusion Proteins

KW - Recovery of Function

KW - Schwann Cells

KW - Spinal Cord

KW - Spinal Cord Injuries

KW - Treatment Outcome

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

KW - Research Support, U.S. Gov't, P.H.S.

M3 - Article

C2 - 12676157

VL - 118

SP - 271

EP - 281

JO - Neuroscience

JF - Neuroscience

SN - 0306-4522

IS - 1

ER -