Solve SCI

Goal: Allow Glial Scar to be Growth-Permissive

Stop Production of Molecules that (potentially) cause gliosis

TNF-alpha

endothelin-1

thrombin

IL-1

IL-6

CNTF

Cytokines

Mitigate effects of glial scar molecules that inhibit neurological regeneration

Phosphacan

Slit proteins

Ephrin B-2

Brevican

Tenascin

Versican

Semaphorin 3

Chondroitin Sulfate Proteoglycans

Removing or preventing the production of sugar epitopes on proteoglycan molecules allows for axonal regeneration. (Bradbury, et al., 2002; Grimpe and Silver, 2004; McKeon, et al., 1995; McKeon, et al., 1991; Steinmetz, et al., 2005)

Enzyme which degrades Chondroitin Sulfate Proteoglycan shows local efficacy in enhancing axonal growth. (Cafferty et al., 2007)

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• Chondroitinaise ABC (ChABC) was enzyme used to degrade chondroitin sulfate proteoglycan•Axonal regrowth in lesion but not below it• No significant motor function recovery• Sensory recovery

Injured corticospinal fibers and uninjured serotonergic fibers increase sprouting after enzymatic treatment to remove sugar epitopes (Barritt et al., 2006)

In vivo studies have revealed remarkable long-distance regeneration of adult axons though CNS white matter tracts after enzymatic treatment to digest these proteoglycan side chains (Steinmetz, et al., 2005)

Neurocan

Introduce Growth-Promoting Factors

cAMP & NT-3 combination has been shown to allow regeneration past lesion site

Intrathecally delivered NT-3, NGF, and GDNF can promote axonal regeneration across the dorsal root entry zone (Ramer et al., 2002; Ramer et al., 2000)

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• Intrathecal NT-3, delivered at the time of injury, promoted an upregulation of the growth-associated protein GAP-43 • Regeneration of cholera toxin B-labeled sensory axons across the DREZ and deep into the dorsal horn.• Appearance of ED-1 expressing phagocytes marked end of effective treatment period of NT-3• If treated within treatment period, regeneration continued, but in grey matter, not white.

L-1

Polysialic Acid Neural Cell Adhesion Molecule

Oncomodulin

Extracellular Matrix

A-Cell Product

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•Resorbable acellular porcine xenograft

Remyelenize Axons

RXR agonist 9 cis retinoic acid. (Jeffrey K Huang, Andrew A Jarjour)

Subtopic

NT-3 will not encourage
regeneration after
myelin breakdown.

Cytokines or other growth
factors draw progenitor cells
to site.