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Sustained delivery of thermostabilized chABC enhances axonal sprouting and functional recovery after spinal cord injury.

Publication ,  Journal Article
Lee, H; McKeon, RJ; Bellamkonda, RV
Published in: Proceedings of the National Academy of Sciences of the United States of America
February 2010

Chondroitin sulfate proteoglycans (CSPGs) are a major class of axon growth inhibitors that are up-regulated after spinal cord injury (SCI) and contribute to regenerative failure. Chondroitinase ABC (chABC) digests glycosaminoglycan chains on CSPGs and can thereby overcome CSPG-mediated inhibition. But chABC loses its enzymatic activity rapidly at 37 degrees C, necessitating the use of repeated injections or local infusions for a period of days to weeks. These infusion systems are invasive, infection-prone, and clinically problematic. To overcome this limitation, we have thermostabilized chABC and developed a system for its sustained local delivery in vivo, obviating the need for chronically implanted catheters and pumps. Thermostabilized chABC remained active at 37 degrees C in vitro for up to 4 weeks. CSPG levels remained low in vivo up to 6 weeks post-SCI when thermostabilized chABC was delivered by a hydrogel-microtube scaffold system. Axonal growth and functional recovery following the sustained local release of thermostabilized chABC versus a single treatment of unstabilized chABC demonstrated significant differences in CSPG digestion. Animals treated with thermostabilized chABC in combination with sustained neurotrophin-3 delivery showed significant improvement in locomotor function and enhanced growth of cholera toxin B subunit-positive sensory axons and sprouting of serotonergic fibers. Therefore, improving chABC thermostability facilitates minimally invasive, sustained, local delivery of chABC that is potentially effective in overcoming CSPG-mediated regenerative failure. Combination therapy with thermostabilized chABC with neurotrophic factors enhances axonal regrowth, sprouting, and functional recovery after SCI.

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Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

February 2010

Volume

107

Issue

8

Start / End Page

3340 / 3345

Related Subject Headings

  • Trehalose
  • Spinal Cord Injuries
  • Regeneration
  • Rats, Sprague-Dawley
  • Rats
  • Motor Activity
  • Male
  • Hot Temperature
  • Enzyme Stability
  • Drug Delivery Systems
 

Citation

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Lee, H., McKeon, R. J., & Bellamkonda, R. V. (2010). Sustained delivery of thermostabilized chABC enhances axonal sprouting and functional recovery after spinal cord injury. Proceedings of the National Academy of Sciences of the United States of America, 107(8), 3340–3345. https://doi.org/10.1073/pnas.0905437106
Lee, Hyunjung, Robert J. McKeon, and Ravi V. Bellamkonda. “Sustained delivery of thermostabilized chABC enhances axonal sprouting and functional recovery after spinal cord injury.Proceedings of the National Academy of Sciences of the United States of America 107, no. 8 (February 2010): 3340–45. https://doi.org/10.1073/pnas.0905437106.
Lee H, McKeon RJ, Bellamkonda RV. Sustained delivery of thermostabilized chABC enhances axonal sprouting and functional recovery after spinal cord injury. Proceedings of the National Academy of Sciences of the United States of America. 2010 Feb;107(8):3340–5.
Lee, Hyunjung, et al. “Sustained delivery of thermostabilized chABC enhances axonal sprouting and functional recovery after spinal cord injury.Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 8, Feb. 2010, pp. 3340–45. Epmc, doi:10.1073/pnas.0905437106.
Lee H, McKeon RJ, Bellamkonda RV. Sustained delivery of thermostabilized chABC enhances axonal sprouting and functional recovery after spinal cord injury. Proceedings of the National Academy of Sciences of the United States of America. 2010 Feb;107(8):3340–3345.
Journal cover image

Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

February 2010

Volume

107

Issue

8

Start / End Page

3340 / 3345

Related Subject Headings

  • Trehalose
  • Spinal Cord Injuries
  • Regeneration
  • Rats, Sprague-Dawley
  • Rats
  • Motor Activity
  • Male
  • Hot Temperature
  • Enzyme Stability
  • Drug Delivery Systems