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Thread: Spinal Cord Injury: Progress, Promise, and Priorities (2005)

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    Post Spinal Cord Injury: Progress, Promise, and Priorities (2005)

    http://www.nap.edu/books/0309095859/html/1.html

    An online book regarding Spinal Cord Injury: Progress, Promise, and Priorities, Board on Neuroscience and Behavioral Health (NBH)
    Here are just some excerpts;

    Spinal cord injury research should focus on preventing the loss of function and on restoring lost functions—including sensory, motor, bowel, bladder, autonomic, and sexual functions—with the elimination of complications, particularly pain, spasticity, pressure sores (decubitus ulcers), and depression, with the ultimate goal of fully restoring to the individual the levels of activity and function that he or she had before injury.

    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 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 (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 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).

    And much more on the link above.

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    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- 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.

    Using gene therapy, spinal cord injury researchers have succeeded in introducing growth factors that have led to some recovery of function in rodent models (Blesch and Tuszynski, 2004; Hendriks et al., 2004). The experiments have thus far established the potential value of gene therapy, which can be used alone or in combination with other therapies.

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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. Seven decades later, Richardson and colleagues (1980) found that months after they inserted a segment of a peripheral nerve into a gap in the spinal cord, the cut axons had regrown into the implanted nerve from both stumps of the severed spinal cord. This technique has been validated in studies with optic nerve neurons, which travel long distances between the eye and the brain. When peripheral nerve grafts were attached to the optic nerve stump, retinal axons were induced to regenerate long distances within the grafts and were capable of making functional connections when the grafts ended near their correct targets in the brain (Carter et al., 1989). Similar techniques have been used in the spinal cord. For example, researchers have induced some neuronal regeneration by transplanting peripheral nerve and Schwann cells inside a polymer tube to fill a complete or partial gap in the spinal cords (Bunge, 2001). Today, scientists are continuing to develop a number of different types of bridges that consist not only of peripheral nerves or Schwann cells, but also olfactory ensheathing cells (OECs), stem cells, marrow stromal cells, trophic factors, biomaterials, or some combination thereof.

    A new generation of scaffolds is being developed for the broad field of tissue engineering (Holmes, 2002). The ideal scaffold for use in the repair of a spinal cord injury would be attractive to regenerating axons, a physical conduit for entry and exit, nontoxic and nonimmunogenic, versatile enough to house a wide range of drugs or cell types, and degradable over a time window sufficient for regrowth (Geller and Fawcett, 2002). The types of materials that may potentially be used as scaffolds include naturally occurring materials (e.g., collagen), organic polymers, and inorganic materials. Even more innovative scaffolds are materials that are injected as liquids and that then self-assemble into fibers with diameters of less than 1 micrometer (Silva et al., 2004).

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    Restoration of Impulse Conduction in Demyelinated Axons

    Healthy nerve cells transmit information by conducting impulses along the lengths of their membranes. Impulses are carried by the movement of charged particles (ions) through cellular channels in the axonal membrane, the most prominent being positively charged sodium (Na+) and potassium (K+) ions. This process is facilitated by the myelin sheath, which acts as an insulator to expedite impulse transmission. Myelin is often destroyed by the injury, although nerve axons may remain intact, and so several therapeutic strategies take aim at the surviving axons by endowing them with the capacity to transmit impulses in the absence of myelin (Chudler, 2004).

    One approach is to transplant cells capable of myelination into demyelinated lesions (Kocsis et al., 2002, 2004). Several studies with animal models of spinal cord injury have provided evidence that implanted Schwann cells (cultured and purified) can remyelinate demyelinated axons, restore conduction, and improve function (Bunge and Wood, 2004).
    Restoration of functional conduction across the membrane is still possible, without myelin, by altering channel activity. The drug 4-aminopyridine (fampridine) has been found to be effective in improving conduction in demyelinated axons in animal models (Shi and Blight, 1997). However, the results obtained with a sustained-release form of the drug in human clinical trials have been only modest. One trial showed negative results (van der Bruggen et al., 2001), but other small trials showed some improvements in individuals’ motor function and sensory function (pinprick and light touch) and reductions in spasticity (muscle tone) and pain (Qiao et al., 1997; Potter et al., 1998). The results for the two primary end points—spasticity and global impression of functioning—of the largest and most recent clinical trial (a phase III trial) did not reach statistical significance, according to the sponsor’s website (the results are not yet published). The study did show, however, a positive trend toward less spasticity (Acorda Therapeutics, 2004; Hayes et al., 2004).

    Another therapeutic approach is to target sodium channels in a subtype-specific manner. When axons within the spinal cord are demyelinated, as in individuals with multiple sclerosis, the body inserts new sodium channels into the membrane of axons that have lost their myelin (Craner et al., 2004a,b). This is one example of plasticity, the body’s natural way of trying to adapt to changed conditions and compensating for lost function. Plasticity is not always beneficial, however. Neurons have 10 distinct sodium channels, each of which has different physiological properties. This represents a subtlety of neuronal design that permits different types of neurons to produce different patterns of impulses within the nervous system (Waxman, 2000). Some types of channels produce background levels of activity that can be interpreted by the brain as pain, whereas others allow large fluxes of sodium that can trigger axonal degeneration. The development of medications that selectively enhance or inhibit the actions of specific subtypes of sodium channels may make it possible to adjust the balance of the channels to preserve normal axon function without silencing them.

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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.

    Proprioception is an often overlooked sensation that is critical in coordinating walking and other movements (Box 5-1). Muscles and joints have special sensory neurons designed to signal the CNS about muscle length, the velocity of movements, and the load (or force) being applied. This sensory input is continually used to convey positional sense (awareness of position of the body in space), to trigger spinal reflexes, and to prepare for effective control over movement. Sensory neurons carrying proprioceptive information course from the muscles and joints directly into the spinal cord. There they project to motor neurons in the spinal cord or they course to the brain (through several synapses). The fibers forming the first part of the pathway, from the muscles to the spinal cord, appear to possess recep- tors for a specific neurotrophic factor known as NT-3 (McMahon et al., 1994).

    In one of the first experiments of its kind, researchers applied NT-3 directly onto the spinal cords of rats (intrathecally) whose sensory fibers had been cut near the entry point into the spinal cord. The cut end of the nerve regrew into the spinal cord and reconnected with target cells at the appropriate level. Not only were the new synapses anatomically correct, but proprioceptive functioning was restored behaviorally and physiologically (Ramer et al., 2002). In a separate set of experiments, patients with a disease that causes demyelination in the peripheral nervous system were given NT-3. This treatment led to improved sensation, a return of the reflexes, and peripheral axon regeneration (Sahenk, 2003). Thus, there is a need to explore the use of neurotrophic factors for promotion of the regrowth of the sensory fibers.

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    Stem Cells And Other Cell-based Therapies

    Cell-based therapies hold great potential as a means of replacing cells and restoring function that has been lost because of a disease or an injury. The application of cell-based therapies to spinal cord injuries is a natural outgrowth of research in other fields, such as cancer, diabetes, and heart disease. 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).

    The Promise of Schwann Cells and Olfactory Ensheathing Cells

    For more than a decade, researchers have known that Schwann cells, the ensheathing cells ordinarily found only in the peripheral nervous system, migrate into the spinal cord after it is injured. Thus, Schwann cells may be used in potential therapies for spinal cord injuries whether they are endogenous or transplanted (Bunge and Wood, 2004). There they may help stimulate axonal growth and myelinate the newly grown axons. The use of Schwann cells is attractive because they are readily accessible and proliferate rapidly in cell culture—up to 100,000 times—and do not trigger an immune response, as long as the individual’s own Schwann cells are used. One problem, however, is that regrowing axons do not exit and grow substantially beyond the site of the Schwann cell implant without the use of other interventions. This problem has led to research focusing on combination strategies, discussed later in this chapter, and has spurred the use of another type of ensheathing cell, OECs. These are specialized types of glial cells that wrap bundles of sensory nerve fibers as they extend from the olfactory mucosa of the nose to the brain’s olfactory center (the olfactory bulb) into the outer layer of the olfactory bulb (for a review, see Raisman, 2001). One role of OECs is to form channels to guide the axonal growth of olfactory neurons from the nose to the brain (Williams et al., 2004). Olfactory neurons are unusual because they are continually being replenished by stem cells in the nasal mucosa throughout adulthood. Axons of the new neurons need to be steered toward their destination by the OECs. Although OECs do not normally myelinate individual axons in vivo, they can become myelinating cells when they are grown in tissue culture under certain conditions (Devon and Doucette, 1992). As a result, OECs are viewed as prime candidates to guide axon regrowth and to replace the myelin in the axons of individuals with spinal cord injuries.

    Several experiments have found that when cultured OECs are implanted into an injured spinal cord, they support the regrowth of axons over long distances and restore function (Li et al., 1997, 1998; Ramon-Cueto et al., 1998, 2000; Radtke et al., 2004). Compared to Schwann cells, OECs were not as effective, after implantation into a contused spinal cord, in inducing long-distance axon regrowth and myelination and improving locomotion (Takami et al., 2002), although they may not have survived well in the lesion milieu. An advantage of OECs is that they intermingle more readily with astrocytes and may be more migratory in the spinal cord than Schwann cells. The disadvantages of OECs are that they do not readily expand in large numbers when they are cultured and are not as readily accessible as Schwann cells. Internationally researchers are attempting to implant fetal olfactory cells into individuals with spinal cord injuries. However, well-designed clinical trials to evaluate this approach have yet to be performed, and there are concerns about safety and efficacy (see Chapter 6) (Lev, 2004; Judson, 2005). Nevertheless, although both Schwann cells and OECs appear to improve function, the mechanisms are not fully understood.

    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).
    Stem cell biology is a quickly evolving field, and much remains to be learned about the use of stem cells in regenerative therapies for spinal cord injuries. Important advances in the understanding of the biology of stem cells are being made in many areas of research. It is becoming clear that many types of adult stem cells have a multilineage potential to give rise to cells that during development are normally derived from a different lineage. For instance, stem cells found in adult bone marrow (Orlic et al., 2001) and liver (Malouf et al., 2001) are capable of generating muscle cells in the heart, and adult hepatic stem cells have the capacity to transdifferentiate into pancreatic endocrine hormone-producing cells (Yang et al., 2002). Recently, numerous reports have described the regenerative capability of a number of stem cell sources, including pancreatic islet tissue from the spleen (Kodama et al., 2005). Evidence also suggests that neuronal cells can be derived not only from neuronal stem cells but also from mesenchymal stem cells (Smith, 2004), bone marrow stem cells (Brazelton et al., 2000; Mezey et al., 2000), stem cells surrounding the heart (Drapeau et al., 2004), 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.

    Since the early 1990s it has been known that stem cells with the capacity to form neurons and glial cells also reside in the nervous system (Gage, 2000). Stem cells might be used in the repair of spinal cord injury by replacing spinal cord cells lost to injury or to rescue the host’s spinal cord cells from dying during the second wave of degeneration. Most of the unresolved questions surrounding stem cell research deal with the safety of the transplant procedure itself, the health and survival of the cells, the ability to induce stem cells to differentiate into a stable cell type, the side effects of the process, and the level of functioning that results. Further research in this area is needed to answer these questions.

    Over the past 5 years, a number of studies, mostly with animal models, have successfully transplanted pure or highly enriched cultures of stem cells for the treatment of spinal cord injuries. Most of those studies found that the stem cells survived after transplantation and led to some degree of myelination, axon regrowth, and functional improvement, directly or indirectly (Table 5-3). Because the methods used varied widely, it is difficult to compare the results of the different studies. For the most part, however, when the recovery of function was measured, it was only modest at best.

    The most commonly studied adult stem cells for the treatment of spinal cord injuries and other neurological conditions are neural stem cells. They are prime candidates for repair of the spinal cord after an injury because they can be isolated and can mature into neurons or glia (oligodendrocytes and astrocytes) in vitro and in vivo (Yandava et al., 1999; Uchida et al., 2000). However, as indicated above, other types of stem cells—including mesenchymal cells, bone marrow cells, and stem cells derived from the

    TABLE 5-3 Animal Studies of Stem Cell Therapies for Spinal Cord Injury

    Reference
    Species
    Stem Cell Source
    Goal
    Results

    McDonald et al. (1999)
    Rats
    Embryonic stem cells from mouse
    To replace neurons and glia
    Embryonic stem cells survived, differentiated, and improved function after implantation into animals with spinal cord injuries.

    Liu et al. (2000)
    Mice
    Embryonic stem cells
    To replace myelin
    Embryonic stem cells survived and differentiated to produce myelin in mice subjected to chemical demyelination. Cells had been directly injected into the spinal cord.

    Akiyama et al. (2002)
    Rats
    Bone marrow stromal cells
    To replace myelin
    Bone marrow cells differentiated into myelinating cells and improved the conduction velocity of nerves of rats subjected to demyelination. The cells were directly injected into the spinal cord.

    (enjoy, Leif)
    Last edited by Leif; 01-03-2006 at 01:28 PM.

  7. #7
    Quote Originally Posted by Leif
    Akiyama et al. (2002)
    Rats
    Bone marrow stromal cells
    To replace myelin
    Bone marrow cells differentiated into myelinating cells and improved the conduction velocity of nerves of rats subjected to demyelination. The cells were directly injected into the spinal cord.
    Dr. Heinrich Cheng has filed a patent for a culture system that generates neurons from bone marrow stem cells.

    Have neurons or neural precursors derived from ESCs been transplanted into a chronic spinal cord injury model and shown significant recovery? This research has to be reproducable by other labs.
    ...it's worse than we thought. it turns out the people at the white house are not secret muslims, they're nerds.

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    You originally said:

    . . . And don’t tell me again here that the spinal cord is super complex, because it is not. It is just some biological signal fibres running up and down inside a bony structure to take care of the electrical current signals and I’m surprised that the science on this field has not advanced more than it has.

    I have read much of this data in various sites previously. Do you still think the spinal cord is not very complex? What you have posted is what is known to date, there is still quite a bit to learn.

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    Quote Originally Posted by Schmeky
    You originally said:

    . . . And don’t tell me again here that the spinal cord is super complex, because it is not. It is just some biological signal fibres running up and down inside a bony structure to take care of the electrical current signals and I’m surprised that the science on this field has not advanced more than it has.

    I have read much of this data in various sites previously. Do you still think the spinal cord is not very complex? What you have posted is what is known to date, there is still quite a bit to learn.
    Schmeky,
    I know what I did say in a previous thread where we discussed how difficult is it to restore a spinal cord? In fact when I was posting this thread from the online book I was thinking about that thread and you, I was quite sure you would arrest me in this thread due to what I wrote in the other thread (good job LOL).

    I’m not a scientist with my special field in spinal cords; I’m just a humble engineer like you wanting to be cured. Above that I can’t shut my mouth – I have to ask all kinds of question (stupid or smart) to better understand the cord, here on this site with good help from the members like yourself and the good doctor and in other forums as well. By other forums I mean discussions here at home with professors working in the field.

    I believe the cord is complex but I don’t believe it is super complex (but that’s just me). I understand the importance of axons connecting to the right synapses etc. - In fact one professor here at home cautions to move to fast here due to wrong connections as indicated in the article above can cause a lot of pain and I believe none of us wants a cure where we are walking backwards eating a kilogram of Nerontine each day. Here at home I have been and am in contact (sporadic by phone or emails) with five professors working as either neurosurgeons or stem cell researchers. All of them believe that one time there will be some kind of a treatment for spinal cord injuries, of course they can’t say when, but then again who can? And it doesn’t matter as long as they have a qualified believe based upon their knowledge. One is reasonable optimistic and believes he can cure me if it was up to him. When he don’t know as limitations are put on this research.

    I also of course agree with you that there is much to be learned in the field (if not the treatment would have been here) either the learning has to do with more research or learning to put the knowledge the researchers have to put it out into clinical trials. In fact we can see the start of this these days which are very encouraging.

    Also; the good doctor here on this site has said that just 10% of the cord could be sufficient to restore many functions as BBS and walking to some extend. This falls also into my logic if wee look upon the cord as wires and connection transferring electrical signals (I’m an electrical and instrumentation engineer). Let my give you an example why this sounds correct in my ears; if we look at one oil refinery or an oil platform it is just a few cables and wires that is of importance to run the plant, maybe as little as 10% here as well, the rest is just additional safety, lighting, sophisticated control systems etc. Just one wire disconnected within the shut-off system will shut down the entire plant. Likewise if just this wire is reconnected the plant will be up and running again (this has of course also to do with the already existing connections here in my example but then again just a few are needed to be connected to have the plant up and running). I believe this logic goes for the cord as well. Many of those signals are just nice-to-have but of course we want them all at the end.

    By the way there was a lot of interesting reading in this online book above I posted. I have also books here at home I bought dealing with the central nervous system and it is complex I agree but I don’t think it is not doable to fix it as many studies also have shown us. But again I’m not a specialist, and thereby we have to help the specialists to reach our common goal.

    PS. Steven; You quote ASC but writes about ESC, I’m not quite sure that I follow you – can you please explain some more.

    Thanks, Leif
    Last edited by Leif; 01-04-2006 at 12:13 PM.

  10. #10
    Quote Originally Posted by Leif
    PS. Steven; You quote ASC but writes about ESC, I’m not quite sure that I follow you – can you please explain some more.

    Thanks, Leif
    Of course. You quoted three stem cell studies; two embryonic, one adult. The adult study served the same purpose as one of the embryonic ones (i.e., remyelination).

    The other study (embryonic) generated neurons. I was pointing out that Heinrich Cheng believes in a culture media to convert bone marrow stem cells into neurons so much that he thinks he can make money off of it. (And studies have shown generation of neurons from bone marrow.)

    So, my question was just asking if ESCs have done what adult stem cells haven't. If so, have the results been reproduced by another lab (so they can go to trial)?

    The studies you quoted do not prove that they can cure paralysis. I may have missed a study, so I was just wondering.
    ...it's worse than we thought. it turns out the people at the white house are not secret muslims, they're nerds.

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