Table 3. Rodent studies of promising human interventions for spinal cord injury (SCI) repair.
| Intervention | Action | Delivery/Confounds |
|---|---|---|
| Bridges | ||
| Polymers, conduits | Fill cavity; may contain growth substances and cells | Injection of alginate or smart biodegradable fibers may release cells and factors, but timing of release and integration with cord uncertain |
| OEGs* | Inject just above and below lesion or within a matrix into a cystic area | |
| Schwann cell graft | Align axons, migrate, produce trophins | Quantity and quality of cells, associated matrix, ability of axon to travel beyond a bridge are uncertain; could induce scar, tumor |
| Bone marrow stromal/stem cells | Differentiate into matrix cells, neurons, and oligodendroglia; serve as neuronal relays within the bridge, repopulate gray and white matter, provide trophins | Inject |
| Stem/progenitor cells | Cell type needed may not differentiate or integrate; ethical issues for human studies with fetal tissues | |
| Fetal spinal cord | ||
| Injury-induced neurogenesis | ||
| Peripheral nerve micrografts | White-to-gray and gray-to-white matter connections | Technically complex, risky surgery |
| Nogo myelin inhibitor | ||
| Nogo-A antibody | Binds Nogo to block inhibition of axon growth | Injected locally by osmotic CSF pump; immunization with CNS myelin component (e.g., Nogo-66) or injection of activated macrophages |
| Nogo peptide antagonist | Bind to Nogo receptor, blocking inhibition of axon growth by Nogo, MAG,* and OMGP* | Potential for oral administration CSF pump; possible intravenous route |
| Nogo receptor antibody | Bind receptor | |
| Proteoglycan inhibitor | ||
| Chondroitinase | Digests inhibitors to foster axon growth in white matter | Infuse locally above and below edge of injury site |
| Growth cone signaling | ||
| cAMP | Overcomes growth cone inhibitors | Must be taken up by neuron (potential for oral administration) |
| cGMP* | Higher ratio of cAMP/cGMP for axon extension | |
| Rho GTPases | Block inhibitory effect of Mag, OMGP, Nogo A | Provide soon after injury for brief time by local infusion near injury site |
| Neurotrophic factors BDNF,* NT-3 | Limit neuronal apoptosis, aid axonal regeneration and guidance to targets; aid dendritic sprouting and learning mechanisms, such as LTP* | Inject engineered fibroblasts that secrete a trophin; inject or pump factor into CSF |
| Other trophins* | ||
| GDNF, FGF, VEGF, IGF-1 | ||
| Immunophilin | Aid axonal growth and transport | Provide orally or infuse near injury site |
| Inosine (93) | Neurite outgrowth | Oral or intravenous route |
| Electrical stimulation | Activates axonal growth cone | Methods and efficacy in humans uncertain |
| X-irradiation | Decrease number of cells making inhibitory molecules; lessen negative inflammatory cells | Safety and potential negative impact in humans |
| Remyelination | ||
| Neural stem cells | Stimulate to become oligodendrocytes | Must proliferate, differentiate, and migrate to where needed; only travel short distances |
| Oligodendrocyte precursors | Abundant in adult brain | Activated in situ precursors may inhibit growth cone |
| OEGs | Migrate to surround axons | Inject into cord |
| Ventral horn | ||
| Prevent apoptosis of injured or axotomized cells | Neurotrophins, antiapoptotic proteins, caspase inhibitors | CSF infusion |
| Implant neuronal precursors | Replace lower motoneurons | Inject near injury site |
| Reimplant ventral roots from below the lesion into cord above lesion | Regenerate axons into peripheral nerve to muscle, sphincters, bladder | Can reinnervate muscle within 1 month of cervical plexus avulsion in humans |
| Dorsal horn | ||
| Neurotrophins | Prevent small-fiber sprouting that leads to pain; increase large to small fiber ratio | Local infusion or implant cells that secrete agent |
| OEGs | Regenerate sensory axons | Inject at dorsal horn entry zone |
| Combinations of above (Figure 1) | Bridge lesion, aid axons to grow beyond the bridge, and target spinal neurons | Graded timing of interventions; more manipulations increase risk of tissue damage and adverse interactions to substances given |
*
OEG, olfactory ensheathing glial cells; MAG, myelin-associated glycoprotein; OMGP, oligodendrocyte myelin glycoprotein; AMP, adenosine monophosphate; GMP, guanosine monophosphate; BDNF, brain-derived neurotrophic factor; GDNF, glial cell-derived neurotrophic factors; FGF, fibroblast growth factor; VEGF, vascular endothelial growth factor; IGF-1, insulin growth factor-1; LTP, long-term potentiation