Stepping Closer To Nerve Regeneration After Spinal Cord Injury

Bradley T. Lang, PhD Researcher, Jerry Silver Lab Department of Neurosciences Case Western Reserve University School of MedicineMedicalResearch.com Interview with:
Bradley T. Lang, PhD
Researcher, Jerry Silver Lab
Department of Neurosciences
Case Western Reserve University School of Medicine

Medical Research: What is the background for this study? What are the main findings?

Dr. Lang: In the late 1980’s, Jerry Silver, PhD, discovered the presence of chondroitin sulfate proteoglycans in the developing nervous system, which form barriers to prevent aberrant growth. He has been building on this finding for more than 30 years, attempting to understand why the adult spinal cord is incapable of regenerating, or why axons don’t grow where they don’t. He has found that the glial scar, which surrounds the site of neural trauma, is incredibly rich in proteoglycans, which prevent regeneration in the spinal cord. In 2009 we collaborated with a group at Harvard to discover the very first receptor for chondroitin sulfate proteoglycans, protein tyrosine phosphatase-sigma, or PTPsigma.

Medical Research: What are the main findings?

Dr. Lang: The findings in this paper are twofold. We first describe a novel mechanism of regeneration failure, where regenerating axons become stabilized within a gradient of chondroitin sulfate proteoglycan, completely preventing motility. This finding helps explain why axons persist in the vicinity of the glial scar after injury indefinitely, with little to no regeneration potential—they are simply embedded within the scar. We were able to model this interaction in a petri dish to screen for drugs that were capable of promoting motility.

The second finding in the manuscript is the discovery and characterization of a novel peptide therapeutic that binds to the receptor for chondroitin sulfate proteoglycans and releases inhibition. Most importantly, this drug was given systemically, similar to a daily insulin injection, avoiding complications due to direct nervous system infusion/injection. After several weeks of treatment (which began 1 day after injury), rats with severe spinal cord injury regained coordinated locomotion, bladder control, and/or balance. In total, 21/26 treated animals regained some function.

Medical Research: What should clinicians and patients take away from your report?

Dr. Lang: Cautious optimism. We designed this drug to be easily translatable to the human, with a straightforward treatment paradigm and relevant injury model. In addition, the most robust effect was the recovery of bladder function, which is a primary concern of the paralyzed patient population. We now need to confirm that this treatment is safe, first in well-controlled animals studies, and then in humans. We plan to generate a full pharmacologic profile and look for any off-target effects. We are currently raising the necessary capital to perform these experiments.

In addition, we are planning on testing this peptide in rodent models of chronic injury, in addition to combining it with rehabilitation strategies.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Lang: This study verifies that the glial scar, in particular chondroitin sulfate proteoglycans, is a major impediment to regeneration in the nervous system.

While it is easy to follow the beaten path and perform experiments similar to those that have been done before, try to keep an open mind. While the risk of failure and negative results is high, any success is potentially groundbreaking.

As the chondroitin sulfate proteoglycans are also a barrier to functional repair in myocardial ischemia, multiple sclerosis, traumatic brain injury, this peptide may have efficacy in additional models of disease.

Citation:

Modulation of the proteoglycan receptor PTPs promotes recovery after spinal cord injury
Bradley T. Lang,Jared M. Cregg,  Marc A. DePaul,Amanda P. Tran,Kui Xu,Scott M. Dyck,Kathryn M. Madalena,Benjamin P. Brown,Yi-Lan Weng,  Shuxin Li,Soheila Karimi-Abdolrezaee,Sarah A. Busch,Yingjie Shen & Jerry Silver

Nature (2014) doi:10.1038/nature13974
Published online 03 December 2014

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