Spinal Cord Injury Progress, Promise, and Priorities (2005) / Chapter Skim
Currently Skimming:
5 Progress Toward Neuronal Repair and Regeneration
5 Progress Toward Neuronal Repair and Regeneration
Pages 121-151
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As research proceeds to refine and improve current therapies, it also generates creative approaches for curing spinal cord injuries. The research strategies and therapeutic approaches described here will both benefit from and inform basic and clini 121
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Many different therapeutic approaches have been tested in vitro or with animal models of spinal cord injury (Table 5-1)
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Rats injected with the activated macrophages showed improved axon regrowth and motor function. A clinical trial based on the results of the work by Rapalino and colleagues was then initiated (Bomstein et al., 2003; Proneuron Biotechnologies, 2004)
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and have been found to significantly reduce the numbers of macrophages and neutrophils at the site of injury when they are administered to rodents after a spinal cord injury. Rats that received this antibody also showed improved proprioception and locomotion, significant decreases in autonomic dysreflexia, and less pain (Mabon et al., 2000; Bao et al., 2004)
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. Another protease, calpain, also plays a role earlier in the biochemical cascade that leads to spinal cord injury-induced apoptosis and thus represents another target for the treatment of spinal cord injuries.
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Several trophic factors have successfully been introduced by injection or by minipumps in animal models of spinal cord injury: brain-derived neurotrophic factor (BDNF) , neurotrophic factor-3 (NT-3)
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. CHRONIC INJURY Removal of Barriers to Axon Regrowth After spinal cord injury there are many barriers that prevent the regrowth of axons.
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act through the same receptor, receptor blockade has the advantage of simultaneously inhibiting more than one inhibitory substance. A follow-up experiment successfully adapted NEP1-40 for injection up to 2 weeks after a spinal cord injury, with some recovery of locomotion (Li and Strittmatter, 2003)
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Axon regrowth can also be stimulated by a variety of growth factors and other agents that enhance growth. Agents found to be successful in animal models are the purine nucleotide inosine (Benowitz et al., 1999)
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Gene therapy is not a current treatment for spinal cord injuries but is being studied with animal models of spinal cord injury. The concept is to transfer into the spinal cord a gene encoding a therapeutic protein, such as a growth factor or an axon guid
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. Although most of the research has focused on fibroblasts, other types of cells can be genetically modified, such as stem cells, oligodendrocytes, and Schwann cells.
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Bridging Gaps with Transplantation Spinal cord injury not only leaves a glial cell scar but also leaves a physical gap. As early as 1906, a peripheral nerve was transplanted into the brain to see if CNS axons would regrow in an environment that was known to be supportive of axonal growth in the peripheral nervous system.
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. Several studies with animal models of spinal cord injury have provided evidence that implanted Schwann cells (cultured and purified)
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Restoration of Sensory Function The loss of sensory modalities can be as debilitating as the loss of motor function. Although sensory function was not previously a substantial focus of spinal cord injury research, scientists are now making progress in understanding what contributes to the loss of sensation and developing treatments to restore sensory modalities, including touch, temperature, pain, proprioception, and feedback control of movements.
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Hematopoietic stem cell-based therapies are now being used routinely to treat certain cancers and are being tested for use in regenerative medicine, for example, to replace insulin-secreting cells destroyed by juvenile diabetes or muscle cells destroyed by heart attacks. Therapies are being developed to restore function in individuals with spinal cord injuries by transplanting many different types of cells, including Schwann cells and OECs to restore nerve conduction, genetically engineered cells to restore trophic support and support regrowth, and stem cells that have the capacity to improve function through a number of mechanisms (Hulsebosch, 2002)
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The Promise of Stem Cells Stem cell therapy holds a seemingly boundless potential for the repair of spinal cord injuries, but research is still in the early stages. The interest arises from stem cells' defining characteristics: their ability to replace themselves by cell division and their versatility, that is, their ability to mature into one or other more specialized cell types (NRC, 2002)
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, and other types of stem cells. Therefore, it is critical that researchers developing stem cell-based therapies to restore function after a spinal cord injury integrate knowledge garnered from other fields of stem cell biology.
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and cells and animals The stem of Stem they and Neural factors sensory The spinal cord Implanted cells differentiate, locomotor Stem They site neurons the in to growth less neurons trophic host's antigen- cells a and their system delivery for as regrowth replace glia scaffolding secrete act develop To and channel with To factors axon To presenting immune To invasive method line line from from from cell cell cells cells cells mouse mouse cells hippocampus stem stem stem rat Neural neonatal Neural neonatal Dendritic Neural fetal Rats Rats Mice Rats (2004)
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As researchers gain additional insights into the mechanisms of neuronal repair and regeneration, efforts to move these discoveries into clinically meaningful therapies will continue. One of the major themes arising from this chapter is that, owing to its complexity, a spinal cord injury is unlikely to be cured by a single therapy.
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One of the major challenges with the development of combination therapies is determination of the specific therapies that can be combined safely and that in concert will provide the greatest efficacy for the treatment of spinal cord injuries. This is a major impediment, because for most complications associated with a spinal cord injury there are multiple experimental approaches to alleviate the complication.
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Further details on the nature and extent of the funding and infrastructure for spinal cord injury research are provided in Chapter 7. A note of caution is needed, as one of the concerns regarding experimental therapies for spinal cord injuries has been the willingness by some patients to try unvalidated experimental therapies before the interventions have been thoroughly tested for safety and efficacy in methodologically rigorous studies.
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As more is learned about the pathways of the molecular and cellular events that result from a spinal cord injury, further therapeutic targets can be identified and approaches to promoting repair and restoring function can be refined. RECOMMENDATIONS Recommendation 5.1: Increase Efforts to Develop Therapeutic Interventions The National Institutes of Health, other federal and state agencies, nonprofit organizations, and the pharmaceutical and medical device industries should increase research funding and efforts to develop thera peutic interventions that will prevent or reverse the physiological events that lead to chronic disability and interventions that are applicable to chronic spinal cord injuries.
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2004. Gene therapy and cell transplantation for Alzheimer's disease and spinal cord injury.
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2004. Chondroitinase ABC enhances axonal regrowth through Schwann cell-seeded guidance channels after spinal cord injury.
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1997. Cellular delivery of neurotrophin 3 promotes corticospinal axonal growth and partial functional recovery after spinal cord injury.
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2001. Neurotrophic factors, cellular bridges and gene therapy for spinal cord injury.
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2003. Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury.
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2004. cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury.
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2003. Calpain inhibitor prevented apoptosis and maintained transcription of proteolipid protein and myelin basic protein genes in rat spinal cord injury.
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2002. Functional recovery following traumatic spinal cord injury mediated by a unique poly mer scaffold seeded with neural stem cells.
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