Chondroitinase improves anatomical and functional outcomes after primate spinal cord injury

Inhibitory chondroitin sulfate proteoglycans (CSPGs) in the extracellular matrix hinder axonal regeneration after spinal cord injury (SCI). In particular, CSPGs form ‘peri-neuronal nets’ that may limit axonal regrowth and synaptic plasticity. Moreover, CSPGs are newly synthesized at sites of central nervous system injury and directly block axon growth. Administration of the enzyme chondroitinase (Chase) degrades inhibitory portions of CSPGs and improves axonal sprouting and functional recovery after SCI in rodents. Here we show for the first time that Chase treatment is also effective in a non-human primate model of SCI. Adult rhesus monkeys received C7 spinal cord lateral hemisection lesions. Four weeks later, subjects received intraparenchymal spinal cord injections of 20 U/ml Chase (or saline) caudal to the lesion. Five µl of Chase / saline were injected at each of 10 sites (spaced 1.5 mm apart in the rostrocaudal axis) on the right side of the spinal cord from C7-T1. This effectively targets spinal cord circuits below the lesion that control hand function. Hand function and locomotion were assessed weekly in a large enriched environment and in a cage-based Brinkman task (retrieval of small food items from wells in a board). Corticospinal axons were labeled with dextran-conjugated tracer injections into right and left motor cortices 6 weeks before sacrifice.
Chase-treated monkeys recovered hand function (but not locomotion) better than control monkeys (Condition x Time, P<0.001, Linear Mixed Model [LMM]). The fact that the beneficial effect is specific to hand function is consistent with the hypothesis that Chase increases axonal sprouting in the treated region (segments C7-T1). Indeed, Chase increased corticospinal axon growth (P=0.036, LMM) and the number of corticospinal synapses (P=0.001, LMM) in gray matter caudal to the lesion. Thus, intraparenchymal Chase is an effective treatment in a primate model of SCI that recapitulates some aspects of traumatic human SCI. Chase treatment for SCI therefore warrants further research and translational development.

Authors: *E. S. ROSENZWEIG1, E. A. SALEGIO2, J. J. LIANG1, J. L. WEBER1, C. WEINHOLTZ1, J. H. BROCK1,3, R. MOSEANKO2, S. HAWBECKER2, R. PENDER2, J. F. IACI4, A. O. CAGGIANO4, A. R. BLIGHT4, B. HAENZI5, J. R. HUIE6, L. A. HAVTON7, Y. S. NOUT-LOMAS8, J. W. FAWCETT5, A. R. FERGUSON6, M. S. BEATTIE6, J. C. BRESNAHAN6, M. H. TUSZYNSKI1,3;
1Neurosciences, Univ. of California San Diego Dept. of Neurosciences, La Jolla, CA; 2California Natl. Primate Res. Ctr., Univ. of California, Davis, Davis, CA; 3VAMC, La Jolla, CA; 4Acorda Therapeutics, Inc., Ardsley, NY; 5Cambridge Univ., Cambridge, United Kingdom; 6Dept. of Neurolog. Surgery, Brain and Spinal Injury Ctr. (BASIC), UCSF, San Francisco, CA; 7Dept. of Neurol., UCLA, Los Angeles, CA; 8Col. of Vet. Med. and Biomed. Sci., Colorado State Univ., Fort Collins, CO
Disclosures: E.S. Rosenzweig: None. E.A. Salegio: None. J.J. Liang: None. J.L. Weber: None. C. Weinholtz: None. J.H. Brock: None. R. Moseanko: None. S. Hawbecker: None. R. Pender: None. J.F. Iaci: A. Employment/Salary (full or part-time):; Acorda Therapeutics, Inc. A.O. Caggiano: A. Employment/Salary (full or part-time):; Acorda Therapeutics, Inc. A.R. Blight: A. Employment/Salary (full or part-time):; Acorda Therapeutics, Inc.. B. Haenzi: None. J.R. Huie: None. L.A. Havton: None. Y.S. Nout-Lomas: None. J.W. Fawcett: F. Consulting Fees (e.g., advisory boards); Acorda Therapeutics, Inc.. A.R. Ferguson: None. M.S. Beattie: None. J.C. Bresnahan: None. M.H. Tuszynski: F. Consulting Fees (e.g., advisory boards); Acorda Therapeutics, Inc.

Grant Support
NIH NS042291
VA Gordon Mansfield Consortium
NIH NCRR P51 OD011107-56
Craig H. Neilsen Foundation
Spitzer Family Trust
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
Christopher and Dana Reeve Foundation
Acorda Therapeutics
Medical Research Council

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