5
PROGRESS TOWARD NEURONAL REPAIR AND REGENERATION

As is apparent from the information presented in the previous chapter, in the past several decades there has been significant progress in improving patient survival and emergency care and in expanding the range of rehabilitative options. During this same time period, the breadth and depth of neuroscience discoveries relevant to spinal cord injury have widely expanded the horizons of potential therapies. What once was dogma—that the central nervous system cannot regenerate—has been dismissed. This newly discovered potential for central nervous system (CNS) regeneration and repair has opened up numerous therapeutic targets and opportunities.

The new challenge facing researchers is to harness the expanding knowledge to develop effective treatments to protect and repair the spinal cord and improve or restore altered and lost function. To address this challenge, researchers must focus on a set of strategies to prevent further tissue loss, maintain the health of living cells and replace cells that have died through apoptosis or necrosis, grow axons and ensure functional connections, and reestablish synapses that restore the neural circuits required for functional recovery.

This chapter highlights the inroads that are being made in experimental settings to develop therapies that will reduce the effects of acute, secondary, and chronic injury and eventually provide cures. 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-



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Spinal Cord Injury: Progress, Promise, and Priorities 5 PROGRESS TOWARD NEURONAL REPAIR AND REGENERATION As is apparent from the information presented in the previous chapter, in the past several decades there has been significant progress in improving patient survival and emergency care and in expanding the range of rehabilitative options. During this same time period, the breadth and depth of neuroscience discoveries relevant to spinal cord injury have widely expanded the horizons of potential therapies. What once was dogma—that the central nervous system cannot regenerate—has been dismissed. This newly discovered potential for central nervous system (CNS) regeneration and repair has opened up numerous therapeutic targets and opportunities. The new challenge facing researchers is to harness the expanding knowledge to develop effective treatments to protect and repair the spinal cord and improve or restore altered and lost function. To address this challenge, researchers must focus on a set of strategies to prevent further tissue loss, maintain the health of living cells and replace cells that have died through apoptosis or necrosis, grow axons and ensure functional connections, and reestablish synapses that restore the neural circuits required for functional recovery. This chapter highlights the inroads that are being made in experimental settings to develop therapies that will reduce the effects of acute, secondary, and chronic injury and eventually provide cures. 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-

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Spinal Cord Injury: Progress, Promise, and Priorities cal research efforts from many related fields of neuroscience, bioengineering, and rehabilitative research. ACUTE INJURY Reduction of Edema and Free-Radical Attack A complex series of biochemical reactions that cause ischemia and edema, followed by necrosis and inflammation, occur as a result of a spinal cord injury. Each reaction could provide a target for early intervention and treatment. The key is to pick out, from among the myriad of reactions, the dominant and most specific players and then target them for treatment. Many different therapeutic approaches have been tested in vitro or with animal models of spinal cord injury (Table 5-1). Some are aimed at TABLE 5-1 Examples of Strategies to Reduce the Effects of Acute Spinal Cord Injuries Tested with Animal Models Strategy Examples of Therapeutic Classes or Agents Reduce ischemia Antivasospasm agents Protein kinase inhibitors Steroids Prevent disruption to the blood-spinal cord barrier Mild to moderate regional hypothermia Reduce calcium influx Blockers of ion channels or exchangers Reduce edema and formation of free radicals Antioxidant enzymes, including free-radical scavengers (e.g., superoxide dismutase, glutathione peroxidase, catalase, and melatonin) Inhibitors of nitric oxide synthase Control inflammation or enhance protective immunity Steroids and other anti-inflammatories (e.g., COX-2 inhibitors and anti-inflammatory cytokines) Activated macrophages and monocytes Inhibitors of immune cell infiltration of the CNS Antibodies against integrin on the vascular surface to prevent egress of neutrophils Reduce tissue loss Cell transplantation (e.g., Schwann cells and olfactory ensheathing cells) Increase intercellular cyclic AMP levels

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Spinal Cord Injury: Progress, Promise, and Priorities TABLE 5-2 Strategies to Block Cell Death Block formation of free radicals Block key proteases (e.g., caspases and calpain) Block cytochrome c release Block glutamate receptors Promote adequate circulation Combination (multipotential) therapies   SOURCE: Dobkin and Havton, 2004. reducing ischemia (from the onset of injury), some are aimed at later events, and some are aimed at more than one event. An emerging strategy, based on more than a decade of study with animal models, takes aim at the formation of free radicals, a crucial step in the onset of necrosis and apoptosis (see the next section) (Table 5-2) (Sugawara and Chan, 2003). Parallel lines of research on stroke and other neurological conditions are being conducted, with opportunities for collaborative efforts. Control of Inflammation or Enhancement of Protective Immunity The immune system’s response to injury has both protective and damaging effects, depending on the cell type, location, and concentration; the timing of the injury; and a host of other factors. One strategy that has been examined is to boost the protective effects of the immune system by injecting animals with T cells that inhibit a protein found in myelin (Hauben et al., 2000). This strategy was found to result in the death of fewer nerve cells. In another attempt to strengthen the immune response, macrophages were implanted into rats at the site of the lesion and distally into the parenchyma (Rapalino et al., 1998). The macrophages were derived from fractions of blood enriched with peripheral blood monocytes incubated with segments of sciatic nerve. 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), and a multisite phase II clinical trial is now being conducted; the results have not yet been published. One contrasting strategy—to blunt the damaging effects of the immune system—is potentially possible with immunosuppressant drugs, such as cyclosporin A and FK506 (tacrolimus). Transplant surgeons have used immunosuppressants to prevent organ rejection for many years, and in recent years these agents have successfully been used as neuroprotective agents in

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Spinal Cord Injury: Progress, Promise, and Priorities animal models of stroke and traumatic brain injury (Kaminska et al., 2004). The drugs are now being tested in animals with spinal cord injuries (Madsen et al., 1998; Bavetta et al., 1999; Diaz-Ruiz et al., 1999, 2000; Nottingham et al., 2002; Akgun et al., 2004). Although their mechanisms of action are not fully known, they may reduce glial cell responses and inflammation (Kaminska et al., 2004). One promising therapy is based on a set of experiments designed to decrease the infiltration of neutrophils and to delay the entry of monocytes into the spinal cord after an injury (Gris et al., 2004). After a spinal cord injury, monocytes and neutrophils bind to a specific protein, VCAM-1, or the CD11d subunit of the CD11d/CD18 integrin on the interior of blood vessels and then egress into the spinal cord. These actions contribute to the inflammatory response and cause considerable secondary damage. Antibodies to VCAM-1 have been developed (Mabon et al., 2000) 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). If the results of these experiments are validated, this therapy could be successfully translated into a clinical trial. Researchers and clinicians have also explored the possibility of cooling the spinal cord. The purpose of this treatment is to minimize the damage caused by apoptosis and the secondary effects of inflammation (Dimar et al., 1999). This approach, which uses extreme levels of total body hypothermia, was extensively studied in the 1960s and 1970s but lost favor in the 1980s because of potential adverse effects, including kidney failure (Inamasu et al., 2003). However, new methods of introducing mild hypothermia have been developed, and hypothermia treatment is once again being considered as a potential treatment for traumatic brain injuries and spinal cord injuries (Dietrich et al., 1994; Yu et al., 2000). Of particular interest are techniques that are under development to precisely control hypothermia to the area of injury beyond several hours (Robertson et al., 1986; Kida et al., 1994; Marsala et al., 1997; Dimar et al., 2000). In patients with cardiovascular and traumatic brain injuries, mild to moderate hypothermia has been reported to improve outcomes (Marion et al., 1997; Jiang et al., 2000; Hypothermia After Cardiac Arrest Study Group, 2002; Bernard et al., 2002). Two studies have examined the efficacy of spinal cord cooling in 18 patients with complete spinal cord injuries (Bricolo et al., 1976; Hansebout et al., 1984). Each of those studies demonstrated that the patients had rates of recovery of sensory and motor functions that were better than expected (Koons et al., 1972; Tator and Deecke, 1973; Negrin, 1975); however, in the 20 years that have followed there has

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Spinal Cord Injury: Progress, Promise, and Priorities been a limited number of clinical trials that have examined this treatment, but they do appear to support the benefit of hypothermia. A 2003 review of all published laboratory experiments of induced hypothermia for the treatment of traumatic spinal cord injuries showed that it offers no benefit for severe injuries but does result in improvements in functional outcomes in individuals with mild to moderate traumatic spinal cord injuries (Inamasu et al., 2003). Induced hypothermia has also been demonstrated to provide functional improvement in rats with ischemic spinal cord injuries (Dimar et al., 2000). SECONDARY INJURY Rescue of Neural Tissue at Risk of Apoptotic Cell Death Neurons near the site of injury may be spared during the acute phase of injury, but they are at risk of dying during the secondary phase. Thus, another target of therapies for spinal cord injuries is to suppress the wave of apoptotic cell death that expands the scope of injury well beyond its original site. Apoptosis involves a complex sequence of biochemical reactions launched inside the cell by a variety of signals, including excessive calcium influx (see Chapter 2). A range of strategies is being tested to prevent apoptosis, primarily in animal models. The strategies fall under the umbrella term neuroprotection, because their goal is to shore up the nervous system’s defenses against the cascade of biochemical threads. Some strategies (e.g., inhibition of free radicals) may block not only apoptosis but also necrosis (Kondo et al., 1997). To add to the complexity, the death of the cell can also lead to the death of an adjacent cell; for example, apoptosis of oligodendrocytes may also induce death of the neurons that they ensheath or adjacent astrocytes (Hulsebosch, 2002). Apoptosis depends heavily on caspases, a group of intracellular proteins that cleave and thereby disable other proteins. Of this group of proteins, caspase-3 and caspase-9 are thought to be dominant players in spinal cord injury-induced apoptosis (Eldadah and Faden, 2000). Inhibition of caspases may therefore be key to preventing apoptosis. Several clinical trials of caspase inhibitors for the treatment of other illnesses are under way (NIH, 2004). 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. Calpain inhibition has successfully prevented neuron death in animal models of spinal cord injury (Ray et al., 2003). Finally, a drug already on the market, the antibiotic minocycline, may alleviate the impact of a spinal cord injury by inhibiting the release of cytochrome c (Teng et al., 2004), a molecule also associated with apoptosis (Di Giovanni et al., 2003).

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Spinal Cord Injury: Progress, Promise, and Priorities Glutamate, a neurotransmitter that is released in excess amounts during a spinal cord injury, can cause potassium to enter the cell, resulting in the death of nearby neurons by necrosis or apoptosis. Glutamate, however, must first bind to receptor proteins that also act as potassium and calcium gates before these ions can enter neurons. Researchers have studied drugs that block glutamate receptors in the hope of preventing excess potassium and calcium from entering and killing the neuron (Lea and Faden, 2003). The results of human clinical trials of glutamate receptor blockade outside the field of spinal cord injury, however, have been disappointing, with little evidence of efficacy (Muir and Lees, 2003). Some blocking strategies have induced rather than prevented cell death (Lea and Faden, 2003). The key to neuroprotection may be more selective targeting of glutamate receptor subtypes, some of which are responsible for activation (e.g., metabotropic glutamate receptors) and others of which are responsible for inhibition (e.g., ionotropic glutamate receptors) (Lea and Faden, 2003; Movsesyan et al., 2004). The effects of erythropoietin in mediating tissue protection after a spinal cord injury have also been explored in laboratory experiments. Erythropoietin is a protein that is primarily responsible for stimulating red blood cell production; however, in animals given erythropoietin immediately after a spinal cord injury, the rate of survival of the neurons responsible for controlling movements increased and the treatment resulted in benefits to neurological function (Celik et al., 2002; Brines et al., 2004). Ongoing studies are attempting to replicate and further explore this approach. Restoration of Trophic Support Neurons need more than oxygen to survive and flourish. Their sustenance depends on trophic factors, which are small proteins secreted by neighboring cells that come into contact with neuronal cell bodies, dendrites, and areas along the length of the axons. 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), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and fibroblast growth factor (FGF), among others (Xu et al., 1995a; Bamber et al., 2001; Jones et al., 2001; Schwab, 2002). The key is to ensure the delivery of the most appropriate factors, as different classes of neurons depend on different trophic factors and some trophic factors may have deleterious effects, such as inducing sensory neurons to become hypersensitive to pain (Krenz and Weaver, 2000). Also key is placement of the appropriate factor at the best anatomical site to deliver levels high enough and continuously enough to keep neurons alive and promote their regrowth. Methods of delivering trophic factors include transplanta-

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Spinal Cord Injury: Progress, Promise, and Priorities 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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Spinal Cord Injury: Progress, Promise, and Priorities administration of PKC inhibitors to rats with spinal cord injuries improves axon regeneration and myelination (Sivasankaran et al., 2004). In another rodent model, researchers degraded CSPGs by administering an enzyme, chondroitinase ABC. Administration of this enzyme promoted the regrowth of axons from spinal cord neurons into grafts of peripheral nerve into the spinal cord (Yick et al., 2004) and growth of CNS axons from grafts of Schwann cells into the spinal cord (Chau et al., 2004). The enzyme treatment also improved locomotion and proprioception (Bradbury et al., 2002; Yick et al., 2004). Schwab (2004) and colleagues pioneered another line of research with animal models that targets the inhibitory molecule Nogo-A, which is expressed on the surface of myelin-forming oligodendrocytes. In 1990, it had been shown that antibodies to Nogo-A led to the regrowth of injured axons over long distances (Schnell and Schwab, 1990). A decade later, after the gene for Nogo-A had been cloned, the researchers developed a safer and more focused strategy: production of large quantities of a partially humanized version of a fragment of the antibody in vitro and then injection of this new antibody as a pure reagent (Brosamle et al., 2000). The results of experiments with mice that lack the Nogo gene (a strategy known as gene knockout) examining axon regrowth and improved gait after injury have varied (Kim et al., 2003). However, experiments performed with rats have shown that injection of the Nogo antibody promotes long-distance axonal regeneration and functional regeneration (Brosamle et al., 2000). A clinical trial of the Nogo antibody is being planned. Because Nogo-A and other inhibitory agents exert their effects through the Nogo receptor, a protein that sits on the external membrane of axons, blockade of the Nogo receptor is another potential way to boost regrowth. GrandPre and colleagues (2002) applied the small peptide NEP1-40 to the injured spinal cord. NEP1-40 binds to, but fails to activate, the Nogo receptor. Those investigators found that receptor blockade leads to substantial regrowth of the disrupted axons. Because Nogo-A and other inhibitory substances (e.g., myelin-associated glycoprotein) 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). A related strategy being explored would target Nogo inhibition at the growing tip of the axon. Once the Nogo receptor is activated, it works through several intermediate reactions within the cell, known as signaling pathways, to block axon regrowth. When researchers targeted one of those intermediate reactions, and thus interrupted the signaling pathway, they found axon regrowth and the recovery of function (Fournier et al., 2003). This treatment was with an agent that inhibited Rho-associated kinase

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Spinal Cord Injury: Progress, Promise, and Priorities (ROCK), an enzyme that appears to dismantle the cell’s internal scaffolding necessary for the growing tip of the axon (Amano et al., 2000). By inhibiting its destructive action, researchers believe that they can prevent the collapse of the growing tip and thus promote axonal extension. A phase I/II clinical trial is currently under way to evaluate the safety, pharmacokinetics, and efficacy of an antagonist to ROCK, Cethrin, in promoting neurogeneration and neuroprotection. Promotion of Axon Regrowth and Guidance For most of the last century, the dogma was that regrowth of nerve axons occurred only in the peripheral nervous system and not in the CNS. Landmark experiments in the early 1980s revolutionized thinking about nerve cells’ capacity for long-distance regeneration. The experiments showed that CNS axon regrowth and connectivity could occur if the CNS environment was changed to match that normally present in peripheral nerves (David and Aguayo, 1981; Keirstead et al., 1989). The previous section highlighted techniques used to overcome the inhibitory environment. This section highlights the axon itself and what treatments might directly boost its regrowth. In reality, the distinction between eliminating the inhibitory effects of glial cells and promoting axon regrowth is blurred, and the techniques are closely intertwined. The promotion of axon regrowth depends, first, on saving the entire neuron from apoptotic cell death (see above). Survival of the whole cell and then promotion of axon regrowth depend on the presence of growth factors in the immediate environment. The majority of these projections remain very short and local to the immediate site of injury. For unknown reasons, however, some fibers are capable of growing long distances around the lesion site. Nevertheless, axon regrowth does not result in improved function unless the axons can stimulate and inhibit the correct cellular target, whether it is in the brain, the spinal cord, or the periphery. If incorrect synapses are formed, pain and spasticity rather than restoration of normal walking and other functions can ensue. 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) and cyclic AMP (Neumann et al., 2002; Qiu et al., 2002). Elevation of cyclic AMP levels by prevention of its normal breakdown can also induce regrowth (Pearse et al., 2004). Whether these agents work directly on the growing tip or more indirectly through the cell’s nucleus is not fully known. Axon regrowth may be necessary, but not sufficient, to regenerate a functional neuronal circuit capable of controlling movements or responding to stimuli. It is also critical that the regrowing axons find their correct

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Spinal Cord Injury: Progress, Promise, and Priorities target cells. During the normal development of an embryo, axons need to be guided to their appropriate targets through the combination of actions of attractive and repulsive axon guidance molecules, such as netrins, semaphorins, slits, and ephrins. Many of these guidance molecules arise from glia (astrocytes and oligodendrocytes), which act as guideposts, and intermediate target cells that steer a growing axon to its appropriate target (Chotard and Salecker, 2004). Each of these molecules also has at least one complementary receptor on the axon. When the guidance molecule and receptor interact, the receptor transmits a signal to the growing axon to either keep growing or avoid the area. These groups of molecules act in complex ways to guide developing axons. Axon guidance relies on the interplay of many different guidance molecules and receptors. Furthermore, the concentration gradients of the molecules also significantly influence the effects of the molecules on steering the axon in a specific direction. The complexity of this mechanism is also underscored by the example of diffusible netrin molecules that, depending on the receptor on the axon with which they interact, can act as either an attractant molecule (Keino-Masu et al., 1996) or a repulsive molecule (Leonardo et al., 1997). Much information has been garnered about how these molecules affect axonal targeting in the developing nervous system; however, studies are under way to determine whether injured axons in the adult CNS are able to reexpress their receptors for these guidance molecules and whether the axonal targets can once again express their guidance cues (Koeberle and Bahr, 2004). Studies to date demonstrate that the expression patterns of many guidance molecules and receptors are the same during nervous system development and after an injury; but some are very different, and these differences could have important consequences on the correct targeting of a growing axon. For instance, the level of expression of a specific class of ephrins (ephrin-Bs) appears to be decreased in the brain, which could limit reinnervation by regenerating axons (Hindges et al., 2002). To overcome this, methods are being developed to examine the effectiveness of using gene therapy strategies and scaffolds (discussed below) to express different combinations of guidance molecules. These guidance molecules could be used as physical conduits that promote regrowth (Dobkin and Havton, 2004). Gene Therapy Gene therapy is another treatment strategy that has great potential to provide the injured spinal cord with the specific gene products—proteins—that it needs to promote functional recovery. 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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Spinal Cord Injury: Progress, Promise, and Priorities ance molecule, or to transplant cells modified to incorporate the gene. When the gene is expressed, the cell makes the desired protein. An advantage of gene therapy over cell replacement therapy is that a specific gene or set of genes can be introduced and the amount (or dose) of the protein can be controlled, which is extremely important in maintaining the fine balance of natural proteins surrounding injured nerve cells and helping guide their growth or regrowth toward target cells in the brain or spinal cord. One of the greatest problems with most therapies is that the dose cannot be readily fine-tuned at the site of injury or along the path of the regrowing axons. Gene therapy can potentially overcome that obstacle. Gene therapy can be used to modulate the amount of protein in a number of ways. One method is to introduce a second gene called a promoter gene along with the therapeutic gene. The promoter gene’s purpose is to turn the therapeutic gene on and off. The promoter gene’s action can also be regulated, for example, with a well-tolerated drug. In one novel example, researchers inserted a promoter gene responsive to the drug tetracycline next to the therapeutic gene, which in this case was the gene for NGF. To activate the production of NGF, the researchers then added a drug similar to tetracycline to the mice’s drinking water. Once it was consumed, the drug turned on the promoter gene, which, in turn, drove the expression of NGF (Blesch et al., 2001). When the researchers wished to minimize or stop the production of NGF, they reduced the dose or removed the drug from the drinking water, thus regulating the amount of NGF needed to stimulate axonal growth. Research to date has focused on the introduction of genes for growth factors (FGF and GDNF) and neurotrophins (BDNF, NGF, NT-3, and NT-4/5). These therapeutic genes are first inserted into fibroblasts (skin cells) in a culture dish. The genetically modified fibroblasts are then implanted directly into the injured area of the spinal cord (a technique known as ex vivo gene therapy). 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. A similar strategy for introducing genes that is being explored is gene therapy. A few important issues for both these strategies are the types of genes to be introduced, how expression of the gene can be limited to specific cell types (which is normally done by using specific gene promoters such as GFAP for astrocytes), and how the gene can be introduced into the cell. One common method of introducing genes is through the use of viruses, but this method can be problematic, because some viruses (such as retroviruses) can only be inserted into dividing cells and most neurons do not divide. Other viruses are used because they specifically target the nervous system, or they can be used to introduce genes into nondividing neurons, but they may also attract a more general immune response that has its own detrimental effects.

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Spinal Cord Injury: Progress, Promise, and Priorities of cyclic AMP and grafts of Schwann cells (Pearse et al., 2004). Rolipram plus embryonic tissue transplants also promote axonal regeneration and functional recovery (Nikulina et al., 2004). This chapter has dealt with more than a dozen approaches that can be used to treat or reverse the impact of a spinal cord injury. Each approach, if successful, would likely only restore partial function, but theoretically they can be pursued together with others to provide maximal recovery of function. For example, cell-based therapies that replace myelin could be combined with treatment with agents that promote axon regrowth, such as neurotrophic factors. 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. Although it is possible for different combinations of drugs to be combined by trial and error, greater progress can be made if specific research efforts are devoted to developing and implementing a mechanism that can be used to select the most likely components that will be required for combination therapies. This requires a strategic approach for screening and assessing the potentials of compounds and therapies to be components of a combination therapy. A second major challenge is determining the appropriate order to apply each of the individual therapies in combinations to maximize the therapeutic value of each treatment. The National Institute of Neurological Disorders and Stroke (NINDS) should play a lead role in developing a strategic approach to the development of combination therapeutic strategies. Furthermore, NINDS, in conjunction with other federal agencies, nonprofit organizations, research centers, and pharmaceutical companies, should examine the challenges that will arise in designing and conducting clinical trials of combination therapies. Some of the issues that need to be addressed include study design and regulatory implications. Other fields of research (e.g., cancer and HIV-AIDS) have dealt with some of the issues involved in testing combination therapies, and lessons should be learned from those efforts. PRIORITIES FOR SPINAL CORD INJURY RESEARCH More knowledge is needed on the optimal targets and pathways on which intervention efforts should be focused. There is still much to be learned about the basic biology of spinal cord injuries (Chapter 2), and as discussed throughout this chapter, numerous potential therapeutic targets are involved in the complex processes of maintaining cell and tissue viabil-

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Spinal Cord Injury: Progress, Promise, and Priorities ity and promoting axonal growth and synaptic integrity to achieve improved and appropriate function (Table 5-4). The addition of information to the body of knowledge on neurological circuitry and mechanisms will be of benefit not only to improving function after a spinal cord injury but also to developing therapies for other neurological diseases and conditions. In the past several decades the breadth and depth of neuroscience discoveries relevant to spinal cord injury have widely expanded the horizons of potential therapies. These new opportunities require increased research support by federal and state agencies, academic organizations, pharmaceutical and device companies, and nonprofit organizations. 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. The committee urges the careful consideration and thorough study of new therapies with the utmost attention to patient safety. TABLE 5-4 Priorities for Spinal Cord Injury Research Develop neuroprotection therapies: identify interventions that promote neuroprotective mechanisms that preserve the spinal cord. Promote axonal sprouting and growth: enhance understanding of the molecular mechanisms that promote and inhibit axonal regeneration—including the roles of glia (astrocytes and oligodendrocytes), scar formation, and inflammation and inhibitory molecules—and develop therapeutic approaches to promote growth. Steer axonal growth: determine the molecular mechanisms that direct axons to their appropriate targets and regulate the formation and maintenance of appropriate synaptic connections. Reestablish essential neuronal and glial circuitry: advance the understanding of the molecular mechanisms that regulate the formation and maintenance of the intricate neuronal and glial circuitry, which controls the complex multimodal function of the spinal cord, including autonomic, sensory, and motor functions. Increase knowledge of the mechanisms that control locomotion, including the differences in the central pattern generator between bipeds and quadrupeds. Prevent acute and chronic complications: develop interventions that prevent and reverse the evolution of events that lead to the wide range of outcomes that result from chronic injury and disability after a spinal cord injury. Maintain maximal potential for recovery: expand the understanding of the requirements for proper postinjury care and rehabilitation that are needed to maintain the maximal potential for full recovery.

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Spinal Cord Injury: Progress, Promise, and Priorities The committee emphasizes the need to use a multifaceted approach to furthering the goal of curing spinal cord injuries. Strategies need to be developed to provide an organized approach to testing therapies in combination. The committee also recognizes that advances in science rely on novel breakthroughs, including those from other fields of research, and that there is a critical need to increase the awareness of spinal cord injury researchers of developments in other fields relevant to spinal cord injuries and to expand innovative approaches to spinal cord injury research. The discussion throughout this chapter emphasizes both the potential for progress and the numerous unknowns in the development of therapies. 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 therapeutic interventions that will prevent or reverse the physiological events that lead to chronic disability and interventions that are applicable to chronic spinal cord injuries. Specifically, research is needed to improve understanding of the basic mechanisms and identify suitable targets to promote neuroprotection, foster axonal growth, enhance axonal guidance, regulate the maintenance of appropriate synaptic connections, and reestablish functional neuronal and glial circuitry; and enhance understanding of proper postinjury care and rehabilitation, such as retraining, relearning, and the use of neuroprostheses, to create the groundwork required to maintain and enhance the maximal potential for full recovery. Recommendation 5.2: Develop a Strategic Plan for Combination Therapeutic Approaches The National Institute of Neurological Disorders and Stroke should develop a strategic plan to screen and assess the potential for compounds and therapies to be used in combination to treat acute and chronic spinal cord injuries.

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