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The Journal of Neuroscience, August 6, 2003, 23(18):7045-7058

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Ex Vivo Adenoviral Vector-Mediated Neurotrophin Gene Transfer to Olfactory Ensheathing Glia: Effects on Rubrospinal Tract Regeneration, Lesion Size, and Functional Recovery after Implantation in the Injured Rat Spinal Cord

Marc J. Ruitenberg,^1 * Giles W. Plant,^2,3 * Frank P. T. Hamers,⁴ Joke Wortel,¹ Bas Blits,¹ Paul A. Dijkhuizen,¹ Willem Hendrik Gispen,⁴ Gerard J. Boer,¹ and Joost Verhaagen¹

¹Graduate School for Neurosciences Amsterdam, Netherlands Institute for Brain Research, 1105 AZ, Amsterdam, The Netherlands, ²Red's Spinal Cord Research Laboratory, School of Anatomy and Human Biology, Clinical Training and Education Center Building, and ³Western Australian Institute for Medical Research, The University of Western Australia, Crawley, Perth, WA 6009, Australia, and ⁴Department of Anatomy and Pharmacology, Rudolf Magnus Institute for Neurosciences, 3584 CG, Utrecht, The Netherlands

The present study uniquely combines olfactory ensheathing glia (OEG) implantation with ex vivo adenoviral (AdV) vector-based neurotrophin gene therapy in an attempt to enhance regeneration after cervical spinal cord injury. Primary OEG were transduced with AdV vectors encoding rat brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or bacterial marker protein -galactosidase (LacZ) and subsequently implanted into adult Fischer rats directly after unilateral transection of the dorsolateral funiculus. Implanted animals received a total of 2 x 10⁵ OEG that were subjected to transduction with neurotrophin-encoding AdV vector, AdV-LacZ, or no vector, respectively. At 4 months after injury, lesion volumes were smaller in all OEG implanted rats and significantly reduced in size after implantation of neurotrophin-encoding AdV vector-transduced OEG. All OEG grafts were filled with neurofilament-positive axons, and AdV vector-mediated expression of BDNF by implanted cells significantly enhanced regenerative sprouting of the rubrospinal tract. Behavioral analysis revealed that OEG-implanted rats displayed better locomotion during horizontal rope walking than unimplanted lesioned controls. Recovery of hind limb function was also improved after implantation of OEG that were transduced with a BDNF- or NT-3-encoding AdV vector. Hind limb performance during horizontal rope locomotion did directly correlate with lesion size, suggesting that neuroprotective effects of OEG implants contributed to the level of functional recovery. Thus, our results demonstrate that genetic engineering of OEG not only resulted in a cell that was more effective in promoting axonal outgrowth but could also lead to enhanced recovery after injury, possibly by sparing of spinal tissue.

Key words: functional recovery; gene therapy; neuroprotection; olfactory ensheathing glia; regeneration; rubrospinal tract; spinal cord injury; viral vectors

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Received Feb. 12, 2003; revised Jun. 3, 2003; accepted Jun. 6, 2003.

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