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Thread: Key advance reported in regenerating nerve fibers

  1. #1
    Senior Member Max's Avatar
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    Key advance reported in regenerating nerve fibers

    Key advance reported in regenerating nerve fibers
    Two-pronged approach synergizes growth
    BOSTON -- Researchers at Children's Hospital Boston and Harvard Medical School have advanced a decades-old quest to get injured nerves to regenerate. By combining two strategies - activating nerve cells' natural growth state and using gene therapy to mute the effects of growth-inhibiting factors - they achieved about three times more regeneration of nerve fibers than previously attained.
    The study involved the optic nerve, which connects nerve cells in the retina with visual centers in the brain, but the Children's team has already begun to extend the approach to nerves damaged by spinal cord injury, stroke, and certain neurodegenerative diseases. Results appear in the February 18th Journal of Neuroscience.

    Normally, injured nerve fibers, known as axons, can't regenerate. Axons conduct impulses away from the body of the nerve cell, forming connections with other nerve cells or with muscles. One reason axons can't regenerate has been known for about 15 years: Several proteins in the myelin, an insulating sheath wrapped around the axons, strongly suppress growth. Over the past two years, researchers have developed techniques that disable the inhibitory action of myelin proteins, but this approach by itself has produced relatively little axon growth.

    http://www.eurekalert.org/pub_releas...-kar021604.php

  2. #2
    Banned Faye's Avatar
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    Thanks Max,

    I'm gonna e-mail them to find out when they expect to start human trials!

    Excerpt:
    The Children's Hospital team, led by Dr. Larry Benowitz, director of Neuroscience Research, reasoned that blocking inhibition alone would be like trying to drive a car only by taking a foot off the brake. "Our idea was to step on the gas - to activate the growth state at the same time," Benowitz said. "Knocking out inhibitory molecules alone is not enough, because the nerve cells themselves are still in a sluggish state."

    The researchers injured the optic nerves of rats, then used a two-pronged approach to get the axons to regenerate. To gas up the sluggish nerve cells, Dr. Dietmar Fischer, first author of the study, caused an inflammatory reaction by deliberately injuring the lens of the eye. Though seemingly harmful, this injury actually stimulates immune cells known as macrophages to travel to the site and release growth factors. As Benowitz's lab had found previously, these growth factors activated genes in the retinal nerve cells, causing new axons to grow into the optic nerve.
    The bold print exemplifies some of the researchers thinking on making a chronic condition acute again, in order to apply a technique that works in acute injuries.

  3. #3
    As some people may remember, Larry Benowitz was the Harvard researcher who discovered that inosine stimulated regeneration of spinal tracts. He has a strong interest in spinal cord injury and continues to work on it but he has also long studied optic nerve regeneration.

    I just did a search for this paper because it did not mention the specific gene therapy that they used. If I remember from talks that he gave, Benowitz had earlier reported a gene associated with regeneration (I believe it was asogenesis factor AF-1, or something like that). In any case, what they did here was to transfect the gene (with a virus) into the eye. When combined with eye injury (which causes neurotrophins to increase), this apparently produced more regeneration but did not restore vision in the rats. Many investigators have shown that injury upregulated neurotrophins and other growth factors in the eye.

    Wise.

    References

    • Benowitz LI, Goldberg DE and Irwin N (2002). Inosine stimulates axon growth in vitro and in the adult CNS. Prog Brain Res. 137: 389-99. Children's Hospital, Laboratories for Neuroscience Research in Neurosurgery, Harvard Medical School, Program in Neuroscience, Department of Surgery, 300 Longwood Avenue, Boston, MA 02115, USA. larry.benowitz@tch.harvard.edu. Unlike mammals, lower vertebrates can regenerate their optic nerves and certain other CNS pathways throughout life. To identify the molecular bases of this phenomenon, we developed a cell culture model and found that goldfish retinal ganglion cells will regenerate their axons in response to the purine nucleoside inosine. Inosine acts through a direct intracellular mechanism and induces many of the changes in gene expression that underlie regenerative growth in vivo, e.g., upregulation of GAP-43, T alpha-1 tubulin, and the cell-adhesion molecule, L1. N-kinase, a 47-49-kDa serine-threonine kinase, may mediate the effects of inosine and serve as part of the modular signal transduction pathway that controls axon growth. In vivo, inosine stimulates extensive axon growth in the mature rat corticospinal tract. Following unilateral transection of the corticospinal tract, inosine applied to the intact sensorimotor cortex stimulated layer 5 pyramidal cells to upregulate GAP-43 expression and to sprout axon collaterals. These collaterals crossed the midline at the level of the cervical enlargement and reinnervated regions whose normal connections had been served. Further understanding of the molecular changes that lie upstream and downstream of N-kinase may lead to new insights into the control of axon growth and to novel methods to improve functional outcome in patients with CNS injury.

    • Benowitz LI, Goldberg DE and Irwin N (2001). A purine-sensitive mechanism regulates the molecular program for axon growth. Restor Neurol Neurosci. 19: 41-9. Laboratories for Neuroscience Research in Neurosurgery, Children's Hospital, Boston MA 02115, USA. larry.benowitz@tch.harvard.edu. Axon growth is characterized by a distinctive program of gene expression. We present evidence here that this program is regulated through a purine-sensitive mechanism, and that it can be re-activated in mature CNS neurons to induce extensive axon growth in vitro and in vivo. In dissociated goldfish retinal ganglion cells, the purine nucleoside inosine acts intracellularly to stimulate axon outgrowth by inducing the expression of GAP-43, Talpha-1 tubulin, and other growth-associated proteins. The purine analog 6-thioguanine (6-TG) acts in the opposite fashion, blocking axon growth and the underlying program of molecular changes. Prior studies in PC12 cells have shown that 6-TG selectively inhibits the activity of N-kinase, a 47-49 kDa serine-threonine kinase. Inosine acts as a competitor of 6-TG, suggesting that it acts as an N-kinase agonist, and that this kinase is part of a modular signal transduction pathway controlling axon growth. Following unilateral transections of the corticospinal tract in mature rats, inosine applied to the intact sensorimotor cortex stimulated layer 5 pyramidal cells to upregulate GAP-43 expression and to sprout axon collaterals that crossed the midline and reinnervated regions of the cervical spinal cord which had lost their normal afferents. It will now be important to identify the molecular changes that lie upstream and downstream of N-kinase, and to explore the clinical potential of activating this pathway in patients who have sustained CNS injury.

    • Benowitz LI, Goldberg DE, Madsen JR, Soni D and Irwin N (1999). Inosine stimulates extensive axon collateral growth in the rat corticospinal tract after injury. Proc Natl Acad Sci U S A. 96: 13486-90. Department of Neurosurgery, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. benowitz@al.tch.harvard.edu. The purine nucleoside inosine has been shown to induce axon outgrowth from primary neurons in culture through a direct intracellular mechanism. For this study, we investigated the effects of inosine in vivo by examining whether it would stimulate axon growth after a unilateral transection of the corticospinal tract. Inosine applied with a minipump to the rat sensorimotor cortex stimulated intact pyramidal cells to undergo extensive sprouting of their axons into the denervated spinal cord white matter and adjacent neuropil. Axon growth was visualized by anterograde tracing with biotinylated dextran amine and by immunohistochemistry with antibodies to GAP-43. Thus, inosine, a naturally occurring metabolite without known side effects, might help to restore essential circuitry after injury to the central nervous system.

    • Schwalb JM, Gu MF, Stuermer C, Bastmeyer M, Hu GF, Boulis N, Irwin N and Benowitz LI (1996). Optic nerve glia secrete a low-molecular-weight factor that stimulates retinal ganglion cells to regenerate axons in goldfish. Neuroscience. 72: 901-10. Department of Neurosurgery, Children's Hospital, Boston, MA 02115, USA. The ability of lower vertebrates to regenerate an injured optic nerve has been widely studied as a model for understanding neural development and plasticity. We have recently shown that, in goldfish, the optic nerve contains two molecules that stimulate retinal ganglion cells to regenerate their axons in culture: a low-molecular-weight factor that is active even at low concentrations (axogenesis factor-1) and a somewhat less active polypeptide of molecular weight 10,000-15,000 (axogenesis factor-2). Both are distinct from other molecules described previously in this system. The present study pursues the biological source and functional significance of axogenesis factor-1. Earlier studies have shown that cultured goldfish glia provide a highly favorable environment for fish or rat retinal ganglion cells to extend axons. We report that the glia in these cultures secrete high levels of a factor that is identical to axogenesis factor-1 in its chromatographic properties and biological activity, along with a larger molecule that may coincide with axogenesis factor-2. Axogenesis factor-1 derived from either goldfish glial cultures or optic nerve fragments is a hydrophilic molecule with an estimated molecular weight of 700-800. Prior studies have reported that goldfish retinal fragments, when explanted in organ culture, only extend axons if the ganglion cells had been "primed" to begin regenerating in vivo for one to two weeks. However, axogenesis factor-1 caused the same degree of outgrowth irrespective of whether ganglion cells had been induced to regenerate new axons in vivo. Moreover, ganglion cells primed to begin regenerating in vivo continued to extend axons in culture only when axogenesis factor-1 was present. In summary, this study shows that glial cells of the goldfish optic nerve secrete a low-molecular-weight factor that initiates axonal regeneration from retinal ganglion cells.

  4. #4
    Senior Member Max's Avatar
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    KEY advance reported in regenerating nerve fibers

    KEY advance reported in regenerating nerve fibers
    Innovations-Report - Germany
    ... in the retina with visual centers in the brain, but the Children's
    team has already begun to extend the approach to nerves damaged by spinal
    cord injury, ...
    http://www.innovations-report.com/ht...ort-25961.html

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    Senior Member Max's Avatar
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    Boston Life Sciences' Collaborating Scientists Demonstrate Key Role of Nerve Cell Activation in Axon Regeneration

    Boston Life Sciences' Collaborating Scientists Demonstrate Key Role of Nerve Cell Activation in Axon Regeneration

    BOSTON--(BUSINESS WIRE)--Feb. 18, 2004--
    Nerve cell activation using Company's proprietary molecules play pivotal role when added to Nogo inhibition in optic nerve regeneration in animals



    Boston Life Sciences, Inc. (NASDAQ: BLSI) announced that the Company's collaborating scientists have shown in animal studies that to achieve extensive optic nerve regeneration requires activation of the intrinsic axonal growth program in optic nerve cells, in addition to suppressing the activity of the Nogo receptor. In the study, published in the current issue of Journal of Neuroscience, activation of the intrinsic growth program of the optic nerve cells was achieved through the use of BLSI's Macrophage Factor, one of BLSI's three proprietary axonal growth stimulators.

    Larry Benowitz of Children's Hospital and Harvard Medical School (and a Principle Collaborating Scientist of BLSI) and colleagues evaluated the contribution to optic nerve regeneration of suppressing Nogo (which inhibits such regeneration; see below), and of stimulating the axonal growth program. Naturally-occurring inhibitory proteins (that act to prevent axon regrowth) have long been considered by many neuroscientists to be the most important explanation for the failure of axonal regeneration to take place after injury to the Central Nervous System (CNS). Prominently among these well-known inhibitors is Nogo, which interacts with its receptor (NgR) to prevent CNS axon regeneration. However, previously published studies by Dr. Benowitz and colleagues have shown that the intrinsic inhibition by Nogo and other inhibitory proteins may be overcome by administering certain axonal growth stimulators (discovered by Dr. Benowitz and colleagues and licensed to BLSI). These stimulators, if administered in the appropriate
    http://home.businesswire.com/portal/...21&newsLang=en

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