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The Journal of Neuroscience, November 1, 2000, 20(21):8061-8068
Regeneration of Lesioned Corticospinal Tract Fibers in the Adult
Rat Induced by a Recombinant, Humanized IN-1 Antibody Fragment
Christian
Brösamle1,
Andrea B.
Huber1,
Markus
Fiedler2,
Arne
Skerra2, and
Martin E.
Schwab1
1 Brain Research Institute, Department of
Neuromorphology, University of Zurich and Swiss Federal Institute of
Technology, 9057 Zurich, Switzerland, and 2 Lehrstuhl
für Biologische Chemie, Technische Universität
München, D-85350 Freising-Weihenstephan, Germany
Axons in the CNS of higher vertebrates generally fail to regenerate
after injury. This lack of regeneration is crucially influenced by
neurite growth inhibitory protein constituents of CNS myelin. We have
shown previously that a monoclonal antibody (mAb IN-1) capable of
binding and neutralizing Nogo-A, a myelin-associated inhibitor of
neurite growth, can induce long-distance axonal regeneration and
increased structural plasticity with improved functional recovery in
rat models of CNS injury. In this paper we demonstrate that a partially
humanized, recombinant Fab fragment (rIN-1 Fab) derived from the
original mAb IN-1, was able to promote long-distance regeneration of
injured axons in the spinal cord of adult rats. When infused into a
spinal cord injury site, regrowth of corticospinal fibers in 11 of 18 animals was observed after a survival time of 2 weeks. Regenerating
fibers grew for >9 mm beyond the lesion site and arborized profusely
in the distal cord. Regenerated fibers formed terminal arbors with
varicosities in the spinal cord gray matter, strongly resembling
synaptic points of contact to neurons in the spinal cord distal to the
lesion. In animals that had received a bovine serum albumin solution or
a recombinant IN-1 fragment that had been mutated in the antigen
binding site (mutIN-1 Fab), no significant growth beyond normal
lesion-induced sprouting was observed. Neutralization of endogenous
nerve growth inhibitors represents a novel use of recombinant antibody
technology with potential therapeutic applications after traumatic CNS lesions.
Key words:
CNS regeneration; Nogo-A; spinal cord injury; axonal
tracing; recombinant antibody; corticospinal tract; rat
Copyright © 2000 Society for Neuroscience 0270-6474/00/20218061-08$05.00/0
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