tion to the site of injury of cells that have been genetically engineered to release high concentrations of growth factors (Conner et al., 2001; Grill et al., 1997; Menei et al., 1998). Investigators have also found that combination therapy may be the most effective. For example, in a multipronged effort to rescue neurons and promote their regrowth, marrow stromal cells delivered in combination with growth factors and cyclic AMP have been found to be more effective than each individual treatment alone (Lu et al., 2004).

CHRONIC INJURY

Removal of Barriers to Axon Regrowth

After spinal cord injury there are many barriers that prevent the regrowth of axons. Several experimental therapeutic strategies take aim at these events, including treatment with antibodies directed to growth-inhibiting molecules (Schnell and Schwab, 1990), the use of mechanisms to interfere with the signaling pathways activated by inhibitory molecules (Cai et al., 1999), prevention or removal of the glial scar (Stichel et al., 1999), enzyme treatment to remove inhibitory proteoglycan molecules (Bradbury et al., 2002), transplantation of growth-promoting cells (Xu et al., 1995b, 1997; McDonald et al., 1999), and administration of growth-promoting molecules (Ramer et al., 2000).

A glial scar is a pathological hallmark of the chronic phase of injury. The scar may physically block axonal penetration or may release inhibitory molecules that block axon regrowth (Fawcett and Asher, 1999; Silver and Miller, 2004). Wholesale efforts to disrupt the scar by removing glial cells altogether or stopping them from proliferating produce widespread excitotoxicity and complications that arise due to the loss of certain neurotrophic factors (Fawcett and Asher, 1999). Furthermore, elimination of glial cells removes their positive role in nervous system recovery.

Several approaches to reducing the impact of the scar have been tested with animal models. The most promising of these approaches may be blockade or degradation of the inhibitory molecules rather than destruction of the glial cells that produce and secrete them. One experiment targeted the large class of inhibitors known as chondroitin sulfate proteoglycans (CSPGs) (Bradbury et al., 2002). Molecules of this class are up-regulated by the injury and are released by astrocytes within the glial scar. CSPGs are soluble molecules that, once released, contribute to a meshwork around neurons known as the extracellular matrix. CSPGs have been found to block axon regrowth both in vitro and in animal models (Fawcett and Asher, 1999; Silver and Miller, 2004) by increasing the activity of the enzyme protein kinase C (PKC) (Sivasankaran et al., 2004). It has been shown that the



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