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Thread: chronic animal sci studies

  1. #1

    chronic animal sci studies

    what are the strategies , if any. to treat chronics? I just heard a web cast from GERON stating that they had negative results on chronics due to scar tissue. has there been any chronic animal studies with success?
    Last edited by jhope; 11-16-2008 at 05:41 AM.
    Han: "We are all ready to win, just as we are born knowing only life. It is defeat that you must learn to prepare for"

  2. #2
    Quote Originally Posted by jhope View Post
    what are the strategies , if any. to treat chronics? I just heard a web cast from GERON stating that they had negative results on chronics due to scar tissue. has there been any chronic animal studies with success?
    Brief Overview of Recent Studies of Treatments for Chronic Spinal Cord Injury
    Wise Young, Ph.D., M.D.
    Rutgers University
    November 16, 2008

    For many years, few researchers have focused on therapies of chronic spinal cord injury. However, just in the last two years, several groups have committed themselves to doing chronic spinal cord injury studies. I will review the work of several groups who had published studies of chronic spinal cord injury treatments, usually administered at 3 months after injury. Note that 3 months in a rat is probably equivalent to a year in humans. I will describe below the studies that have been published in the past 12 months.

    In 2008, Zurita, et al. [9] reported beneficial effects of bone marrow autografts in pigs with chronic paraplegia, including recovery of somatosensory evoked potentials, confirming the results of previous studies in chronic paraplegic rats. Note that this work was preceded by several studies since 2000, report beneficial effects of various cell transplants on chronic spinal cord injury [10]. In 2001, Zurita, et al. [11] then examined the recovery of function of 70 adult female Wistar rats that had transplants of fetal brain tissues and adult peripheral nerve at 3 months after injury. They found that the transplants appeared to aid long-term anatomical remodeling of the injury site and functional recovery. In 2004, Zurita assessed the effects of bone marrow stromal cell transplants on chronic paraplegic rats and found that the grafted cells survived and there was marked ependymal proliferation. They published a paper in 2006 [8] reporting that bone marrow stromal cells can improve functional and morphological outcome of chronic paraplegic rats.

    Nomura, et al. [7] recently reported studies where they transplanted peripheral neural cells in chitosan channels at 4 weeks after transecting the spinal cord. The chitosan channels plus peripheral nerve cells resulted in a thicker bridge containing myelinated axons.

    Jiang, et al. [5] found remyelination after chronic spinal cord injury is associated with proliferation of adult progenitor cells after systemic administration of guanosine. Guanosine or an analog of guanosine has actually been tried in clinical trials of subacute patients although the results of that trial are not known. In any case, this study suggests that guanosine and its breakdown product guanine accumulated in the spinal cord and was associated with functional improvement and remyelination at 5 weeks after rat spinal cord injury.

    Feng, et al. [4] recently reported that grafts of pre-injured sural nerve (autograft) stimulated recovery of hindlimb motor function in rats after a contusion injury. They observed sprouting and growth of axons across the injury site.

    Lu, et al. [6] reports that administration of autologous bone marrow cells into the spinal cord at 6 weeks after injury (without resection of the “chronic scar” allowed robust axonal regeneration across the lesion site, particularly in animals that received cells that were genetically modified to express NT-3 neutrophins. The chronically regenerating axons preferentially associated with Schwann cell surfaces expressing both inhibitory NG2 substrates and the permissive substrate of L1 and NCAM at the lesion site. They concluded “inhibitory factors deposited at sites of chronic SCI do not create impenetrable boundaries and that inhibition can be balanced by local and diffusible signals to generate robust axonal growth even without resecting chronic scar tissue.”

    Eaton, et al., [3] reported that subarachnoid transplantation of a human neuronal cell line attenuated chronic allodynia and hyperalgesia after excitotoxic spinal cord injury in rats. These are cells that express GABA and glycine, presumably inhibitory neurotransmitters. These studies suggest that potential treatment for chronic neuropathic pain by implantation of inhibitory neurons in to rats with chronic spinal cord injury.

    Cai, et al. [2] used a lactic acid foam with oriented channels to reconnect chronically hemisected spinal cords. They found that large numbers of axons grew into the foam implants and that Schwann cells but no astrocytes migrated through the channels.

    Bravo, et al. [1] studied the effects of inodrenate (a 5-HT1A agonist) on motor performance of rats after chronic spinal cord injury. Indorenate treated rats had much better locomotor function at low doses. They suggest that serotonergic agents could be used to improved function in chronic spinal cord injury.

    So, a number of therapies have now been shown to be effective. I am expecting that there will be more studies in the coming year.

    References Cited
    1. Bravo G, Ibarra A, Guizar-Sahagun G, Rojas G and Hong E (2007). Indorenate improves motor function in rats with chronic spinal cord injury. Basic Clin Pharmacol Toxicol. 100: 67-70. Department of Pharmacobiology, CINVESTAV-IPN, Sede Sur, Mexico. gbravof@yahoo.com. The effect of indorenate (5-methoxytryptamine, beta-methyl carboxylate hydrochloride), a 5-HT1A agonist, was investigated on the motor performance of rats with chronic spinal cord injury. Four months after a ninth thoracic vertebrae spinal cord contusion, 29 rats were randomly allocated into two groups: saline solution and indorenate-treated animals with daily doses incremented at weekly intervals. The locomotor performance of all rats was measured by the Basso, Beattie, and Bresnahan (BBB) rating scale. The results showed that at the end of the treatment, the motor activity of indorenate group was significantly better than that presented by saline solution group. The 80% of indorenate, (against 15% of saline solution) did not show detriment on motor activity. When we analysed the motor activity of rats with basal BBB lower than 10, a significant improvement of motor recovery in indorenate-treated animals was observed. The benefits observed in locomotor function at low doses followed by increasing doses could be associated with pharmacological treatment by indorenate, a well-known 5-HT1A receptor agonist. Our results suggest a potential mechanism by which serotonergic agents may improve motor function in rats with chronic spinal cord injury.
    2. Cai J, Ziemba KS, Smith GM and Jin Y (2007). Evaluation of cellular organization and axonal regeneration through linear PLA foam implants in acute and chronic spinal cord injury. J Biomed Mater Res A. Department of Physiology, University of Kentucky, Lexington, Kentucky 40536-0298. There are few studies of neural implants in spinal cord injury (SCI) focused on supporting directed axon growth. In this study, we fabricated a macroporous poly (lactic acid) (PLA) foam with oriented inner channels. Amorphous foam without linear channels served as a control in an acute SCI injury model, and the effectiveness of foam with linear channels was further investigated in a chronic SCI model. Implants were placed into a 2 mm hemisection lesion cavity at the T8 spinal cord level in adult rats. Two weeks post-implantation, tissue sections including the implants were examined using antibodies against GFAP, p75, ED-1, laminin, GAP-43, and CGRP. Foam implants were well-integrated with the host spinal cord. In linear foams, numerous DAPI-stained cells were found within the inner channels. Schwann cells but not astrocytes had migrated within the channels. Intense laminin staining was observed throughout the extracellular matrix substrate. GAP-43- and CGRP-positive axons grew through the implants following the linear channels. In the amorphous control foams, DAPI staining distributed evenly through the pores. However, the growth of GAP-43 or CGRP-positive axons was misguided and impeded at the entrance area of the foam. Higher numbers of GAP-43 and CGRP-positive axons grew into linear foam implants after chronic SCI than acute SCI. These results suggest the potential application of linear foam implants in cell and axon guidance for SCI repair, especially for chronic SCI. (c) 2007 Wiley Periodicals, Inc. J Biomed Mater Res 2007.
    3. Eaton MJ, Wolfe SQ, Martinez M, Hernandez M, Furst C, Huang J, Frydel BR and Gomez-Marin O (2007). Subarachnoid transplant of a human neuronal cell line attenuates chronic allodynia and hyperalgesia after excitotoxic spinal cord injury in the rat. J Pain. 8: 33-50. VA RR&D Center of Excellence in Functional Recovery in Chronic Spinal Cord Injury, VAMC, Miami, FL, USA. meaton@miami.edu. The relief of neuropathic pain after spinal cord injury (SCI) remains daunting, because pharmacologic intervention works incompletely and is accompanied by multiple side effects. Transplantation of human cells that make specific biologic agents that can potentially modulate the sensory responses that are painful would be very useful to treat problems such as pain. To address this need for clinically useful human cells, the human neuronal NT2 cell line was used as a source to isolate a unique human neuronal cell line that synthesizes and secretes/releases the inhibitory neurotransmitters gamma-aminobutyric acid (GABA) and glycine. This new cell line, hNT2.17, expresses an exclusively neuronal phenotype, does not incorporate bromodeoxyuridine during differentiation, and does not express the tumor-related proteins fibroblast growth factor 4 and transforming growth factor-alpha during differentiation after 2 weeks of treatment with retinoic acid and mitotic inhibitors. The transplant of predifferentiated hNT2.17 cells was used in the excitotoxic SCI pain model, after intraspinal injection of the mixed AMPA/metabotropic receptor agonist quisqualic acid (QUIS). When hNT2.17 cells were transplanted into the lumbar subarachnoid space, tactile allodynia and thermal hyperalgesia induced by the injury were quickly and potently reversed. Control cell transplants of nonviable hNT2.17 cells had no effect on the hypersensitivity induced by QUIS. The effects of hNT2.17 cell grafts appeared 1 week after transplants and did not diminish during the 8-week course of the experiment when grafts were placed 2 weeks after SCI. Immunohistochemistry and quantification of the human grafts were used to ensure that many grafted cells were still present and synthesizing GABA at the end of the study. These data suggest that the human neuronal hNT2.17 cells can be used as a "biologic minipump" for antinociception in models of SCI and neuropathic pain. PERSPECTIVE: This study describes the initial characterization and use of a human-derived cell line to treat neuropathic pain that would be suitable for clinical application, once further tested for safety and approved by the Food and Drug Administration. A dose of these human cells could be delivered with a spinal tap and affect the intrathecal spinal environment for sensory system modulation.
    4. Feng SQ, Zhou XF, Rush RA and Ferguson IA (2008). Graft of pre-injured sural nerve promotes regeneration of corticospinal tract and functional recovery in rats with chronic spinal cord injury. Brain Res. 1209: 40-8. Department of Human Physiology and Centre for Neuroscience, Flinders University School of Medicine, Adelaide SA 5001, Australia. A possible treatment approach for chronic spinal cord injuries has been tested. We report that minced, autologous, pre-injured peripheral nerve administered as a single injection into an injury-induced cyst, resulting from a contusion injury of the thoracic spinal cord, stimulates recovery of hindlimb locomotor function in rats, as measured by the Basso, Beattie, Bresnahan Locomotor Rating Scale. This response was further enhanced by the addition of exogenous neurotrophic factors. Histological analysis showed axons of the corticospinal tract exhibited significant regeneration past the injury site, when quantified both by number and length. Results indicate that the use of a pre-injured peripheral nerve graft stimulates chronically injured descending nerves to overcome a local inhibitory environment. The resulting sprouting and growth past the injury site is associated with a significant improvement in locomotor function.
    5. Jiang S, Ballerini P, Buccella S, Giuliani P, Jiang C, Huang X and Rathbone MP (2008). Remyelination after chronic spinal cord injury is associated with proliferation of endogenous adult progenitor cells after systemic administration of guanosine. Purinergic Signal. 4: 61-71. Department of Surgery (Neurosurgery, Neurobiology), McMaster University, Health Sciences Centre, 4E15, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada, jiangs@mcmaster.ca. Axonal demyelination is a consistent pathological sequel to chronic brain and spinal cord injuries and disorders that slows or disrupts impulse conduction, causing further functional loss. Since oligodendroglial progenitors are present in the demyelinated areas, failure of remyelination may be due to lack of sufficient proliferation and differentiation of oligodendroglial progenitors. Guanosine stimulates proliferation and differentiation of many types of cells in vitro and exerts neuroprotective effects in the central nervous system (CNS). Five weeks after chronic traumatic spinal cord injury (SCI), when there is no ongoing recovery of function, intraperitoneal administration of guanosine daily for 2 weeks enhanced functional improvement correlated with the increase in myelination in the injured cord. Emphasis was placed on analysis of oligodendrocytes and NG2-positive (NG2+) cells, an endogenous cell population that may be involved in oligodendrocyte replacement. There was an increase in cell proliferation (measured by bromodeoxyuridine staining) that was attributable to an intensification in progenitor cells (NG2+ cells) associated with an increase in mature oligodendrocytes (determined by Rip+ staining). The numbers of astroglia increased at all test times after administration of guanosine whereas microglia only increased in the later stages (14 days). Injected guanosine and its breakdown product guanine accumulated in the spinal cords; there was more guanine than guanosine detected. We conclude that functional improvement and remyelination after systemic administration of guanosine is due to the effect of guanosine/guanine on the proliferation of adult progenitor cells and their maturation into myelin-forming cells. This raises the possibility that administration of guanosine may be useful in the treatment of spinal cord injury or demyelinating diseases such as multiple sclerosis where quiescent oligodendroglial progenitors exist in demyelinated plaques.
    6. Lu P, Jones LL and Tuszynski MH (2007). Axon regeneration through scars and into sites of chronic spinal cord injury. Exp Neurol. 203: 8-21. Department of Neurosciences-0626, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Cellular and extracellular inhibitors are thought to restrict axon growth after chronic spinal cord injury (SCI), confronting the axon with a combination of chronic astrocytosis and extracellular matrix-associated inhibitors that collectively constitute the chronic "scar." To examine whether the chronically injured environment is strongly inhibitory to axonal regeneration, we grafted permissive autologous bone marrow stromal cells (MSCs) into mid-cervical SCI sites of adult rats, 6 weeks post-injury without resection of the "chronic scar." Additional subjects received MSCs genetically modified to express neurotrophin-3 (NT-3), providing a further local stimulus to axon growth. Anatomical analysis 3 months post-injury revealed extensive astrocytosis surrounding the lesion site, together with dense deposition of the inhibitory extracellular matrix molecule NG2. Despite this inhibitory environment, axons penetrated the lesion site through the chronic scar. Robust axonal regeneration occurred into chronic lesion cavities expressing NT-3. Notably, chronically regenerating axons preferentially associated with Schwann cell surfaces expressing both inhibitory NG2 substrates and the permissive substrates L1 and NCAM in the lesion site. Collectively, these findings indicate that inhibitory factors deposited at sites of chronic SCI do not create impenetrable boundaries and that inhibition can be balanced by local and diffusible signals to generate robust axonal growth even without resecting chronic scar tissue.
    7. Nomura H, Baladie B, Katayama Y, Morshead CM, Shoichet MS and Tator CH (2008). Delayed implantation of intramedullary chitosan channels containing nerve grafts promotes extensive axonal regeneration after spinal cord injury. Neurosurgery. 63: 127-41; discussion 141-3. Toronto Western Research Institute, Toronto Western Hospital, Toronto, Canada. OBJECTIVE: We describe a new strategy to promote axonal regeneration after subacute or chronic spinal cord injury consisting of intramedullary implantation of chitosan guidance channels containing peripheral nerve (PN) grafts. METHODS: Chitosan channels filled with PN grafts harvested from green fluorescent protein rats were implanted in the cavity 1 week (subacute) or 4 weeks (chronic) after 50-g clip injury at T8 and were compared with similarly injured animals implanted with either unfilled channels or no channels. Functional recovery was measured weekly for 12 weeks by open-field locomotion, after which histological examination was performed. RESULTS: The implanted channels with PN grafts contained a thick tissue bridge containing as many as 35,000 myelinated axons in both the subacute and chronic spinal cord injury groups, with the greatest number of axons in the channels containing PN grafts implanted subacutely. There were numerous green fluorescent protein-positive donor Schwann cells in the tissue bridges in all animals with PN grafts. Moreover, these Schwann cells had high functional capacity in terms of myelination of the axons in the channels. In addition, PN-filled chitosan channels showed excellent biocompatibility with the adjacent neural tissue and no obvious signs of degradation and minimal tissue reaction at 14 weeks after implantation. In control animals that had unfilled chitosan channels implanted, there was minimal axonal regeneration in the channels; in control animals without channels, there were large cavities in the spinal cords, and the bridges contained only a small number of axons and Schwann cells. Despite the large numbers of axons in the chitosan channel-PN graft group, there was no significant difference in functional recovery between treatment and control groups. CONCLUSION: Intramedullary implantation of chitosan guidance channels containing PN grafts in the cavity after subacute spinal cord injury resulted in a thicker bridge containing a larger number of myelinated axons compared with chitosan channels alone. A chitosan channel containing PN grafts is a promising strategy for spinal cord repair.
    8. Zurita M and Vaquero J (2006). Bone marrow stromal cells can achieve cure of chronic paraplegic rats: Functional and morphological outcome one year after transplantation. Neurosci Lett. 402: 51-6. Neuroscience Research Unit of the Mapfre-Medicine Foundation, Neurosurgical Service, Puerta de Hierro Hospital, Autonomus University, San Martin de Porres 4, 28035 Madrid, Spain. Chronic paraplegia resulting from severe spinal cord injury (SCI) is considered to be an irreversible condition. Nevertheless, recent studies utilizing adult stem cells appear to offer promise in the treatment of this and other neurological diseases. Here, we show that progressive functional motor recovery is achieved over the course of the year following the administration of bone marrow stromal cells (BMSC) in traumatic central spinal cord cavities of adult rats with chronic paraplegia. At this time, functional recovery is almost complete and associated with evident nervous tissue regeneration in the previously injured spinal cord.
    9. Zurita M, Vaquero J, Bonilla C, Santos M, De Haro J, Oya S and Aguayo C (2008). Functional recovery of chronic paraplegic pigs after autologous transplantation of bone marrow stromal cells. Transplantation. 86: 845-53. Neuroscience Research Unit, Puerta de Hierro Hospital, San Martin de Porres, 4, 28035-Madrid, Spain. BACKGROUND: Bone marrow stromal cells (BMSC) transplantation offers promise in the treatment of chronic paraplegia in rodents. Here, we report the effect of this cell therapy in adult pigs suffering chronic paraplegia. METHODS: Three months after spinal cord injury, autologous BMSC in autologous plasma was injected into lesion zone and adjacent subarachnoid space in seven paraplegic pigs. On the contrary, three paraplegic pigs only received autologous plasma. Functional outcome was measured weekly until the end of the follow-up, 3 months later. RESULTS: Our present study showed progressive functional recovery in transplanted pigs. At this time, intramedullary posttraumatic cavities were filled by a neoformed tissue containing several axons, together with BMSC that expressed neuronal or glial markers. Furthermore, in the treated animals, electrophysiological studies showed recovery of the previously abolished somatosensory-evoked potentials. CONCLUSIONS: These findings confirm previous observations in rodents and support the possible utility of BMSC transplantation in humans suffering chronic paraplegia.
    10. Zurita M, Vaquero J and Oya S (2000). Grafting of neural tissue in chronically injured spinal cord: influence of the donor tissue on regenerative activity. Surg Neurol. 54: 117-25. Neuroscience Research Unit of the Mapfre-Medicine Foundation, Puerta de Hierro Clinic, Autonomous University, Madrid, Spain. BACKGROUND: To determine the influence of different nervous tissue grafts on the regenerative activity of chronically injured spinal cord, an experimental study examining the expression of the proliferating cell nuclear antigen (PCNA) in chronically injured spinal cord subjected to neural grafting was performed.METHODS: Three months after induced spinal cord injury, paraplegic Wistar rats were subjected to grafting of neural tissue. Grafts consisted of fetal brain cortex, fetal spinal cord, crushed adult peripheral nerve tissue, or fetal brain cortex combined with crushed adult peripheral nerve tissue. Four months later, the spinal cord was removed and the grafted zone was studied by means of immunohistochemical demonstration of PCNA.RESULTS: Different patterns of PCNA expression were recorded in the different experimental groups. PCNA-immunostained cells in injured spinal cord tissue, mainly ependymal cells and astrocytes, increased when co-transplantation of fetal brain cortex and crushed adult peripheral nerve tissue was used, in comparison to other neural donor tissues. In the grafted tissue, proliferative activity was greater when fetal brain cortex, alone or with peripheral nerve, was used, in comparison to the use of fetal spinal cord or adult peripheral nerve tissue. Nevertheless, the number of PCNA-positive cells does not seem to be influenced by the presence of peripheral nerve tissue in the donor tissue. CONCLUSIONS: Our present findings suggest the effectiveness of co-transplantation of peripheral nerve tissue and fetal brain tissue in attempts at spinal cord reconstruction after injury.
    11. Zurita M, Vaquero J, Oya S and Montilla J (2001). Functional recovery in chronic paraplegic rats after co-grafts of fetal brain and adult peripheral nerve tissue. Surg Neurol. 55: 249-54; discussion 254-5. Neuroscience Research Unit of the Mapfre-Medicine Foundation, Puerta de Hierro Clinic, Autonomous University, Madrid, Spain. BACKGROUND: In recent years, experimental studies have sought some type of functional improvement in traumatic paraplegia by transplanting neural tissue into the injured spinal cord. The aim of this work is to study the possibility of functional recovery in chronic paraplegic rats after co-transplantation of fetal cerebral tissue and adult peripheral nerve tissue. METHODS: Seventy adult female Wistar rats were subjected to spinal cord injury at the T6-T8 level, causing complete paraplegia. Three months later, in 50 rats (grafted group) the injured spinal cord tissue received a graft of fetal brain cortex associated with crushed adult peripheral nerve. All the animals (grafted and control groups) were subjected to daily rehabilitation procedures from the first week after the injury, and evaluated weekly for motor and sensory recovery. Statistical analysis of different behavioral data between control and grafted animals was performed using the Kruskal-Wallis ANOVA and the nonparametric Wilcoxon test. RESULTS: Between 8 and 12 months after transplantation, progressive signs of functional recovery were observed in the grafted animals, associated with an increase in muscle mass in the lower extremities, findings that were significantly different from those in nongrafted animals (p < 0.05). At this time, donor cerebral tissue is integrated into previously injured spinal cord and results in formation of bundles of nerve fibers that emerge from the area of the transplant and surround the spinal cord beneath the lesion. CONCLUSIONS: Delayed co-transplantation of fetal cerebral tissue and peripheral nerve tissue can be used to achieve anatomical remodeling and long-term functional recovery in rats rendered paraplegic as result of severe spinal cord injury. These findings support the possibility of functional recovery after chronic traumatic paraplegia.

  3. #3
    Thanks Wise.

    Arg, I wonder why the results of the subacute trial weren't published?

    Jiang, et al. [5] found remyelination after chronic spinal cord injury is associated with proliferation of adult progenitor cells after systemic administration of guanosine. Guanosine or an analog of guanosine has actually been tried in clinical trials of subacute patients although the results of that trial are not known. In any case, this study suggests that guanosine and its breakdown product guanine accumulated in the spinal cord and was associated with functional improvement and remyelination at 5 weeks after rat spinal cord injury.

  4. #4
    Senior Member
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    Dr Young

    I've been following the Dr. Davies thread on Carecure for the last year. In Dec 2007 Dr. Davies was going to start treating chronic rats that were 6 months post injury with decorin. Hasn't Dr. Davies published something about his research? Is this a bad sign or is it too soon to expect this research to be published. I have no idea how long it takes for research to be published.

    Please don't think that I'm putting you on the spot to give your opinion of Dr. Davies research. I'm just anxious because a year ago I was really excited about the prospects for a treatment for chronic SCI.

    Roger
    Last edited by Roger; 11-17-2008 at 07:26 PM.

  5. #5
    Wise,

    you are a plethora of knowledge. I am in awe of you. my biggest fear is the black hole of paperwork and money to get these studies to the bedside. I am hoping geron can be the template for everyone else.
    Han: "We are all ready to win, just as we are born knowing only life. It is defeat that you must learn to prepare for"

  6. #6
    conflicting evidence of without resection of the “chronic scar” allowed robust axonal regeneration across the lesion and Dr.Davies and Dr. Kierstead's studies that claim glial scars cause axonal ''j hooking''.

    In dentistry we have the same conflicting studies as to disc attachment in the TMJ.
    Han: "We are all ready to win, just as we are born knowing only life. It is defeat that you must learn to prepare for"

  7. #7
    Quote Originally Posted by antiquity View Post
    Thanks Wise.
    Arg, I wonder why the results of the subacute trial weren't published?
    • Antiquity, you are very welcome. I guess when companies go out of business in the middle of clinical trials, like Proneuron and Neutrophics (or whatever its name was), the wind goes out of their sails not only for the trial but for the data analysis and paper-writing as well.

    Quote Originally Posted by Roger
    I've been following the Dr. Davies thread on Carecure for the last year. In Dec 2007 Dr. Davies was going to start treating chronic rats that were 6 months post injury with decorin. Hasn't Dr. Davies published something about his research? Is this a bad sign or is it too soon to expect this research to be published. I have no idea how long it takes for research to be published.

    Please don't think that I'm putting you on the spot to give your opinion of Dr. Davies research. I'm just anxious because a year ago I was really excited about the prospects for a treatment for chronic SCI.
    • Dr. Davies presented some of his studies in Beijing and in Hong Kong. I am excited about the prospects of using decorin to treat spinal cord injury. However, I am unsure of his chronic spinal cord injury experiments and that is in part because he uses a hemisection model which is not particularly good for assessing behavior (since most chronic hemisected rats are walking almost normally). In my opinion, decorin needs to be tested in a chronic spinal cord contusion model. He told me that there will be more decorin available for other investigators in the coming months and our laboratory would be very interested in testing it.

    Quote Originally Posted by jhope
    conflicting evidence of without resection of the “chronic scar” allowed robust axonal regeneration across the lesion and Dr.Davies and Dr. Kierstead's studies that claim glial scars cause axonal ''j hooking''.

    In dentistry we have the same conflicting studies as to disc attachment in the TMJ.

    Yesterday 02:45 PM
    jhope Wise,

    you are a plethora of knowledge. I am in awe of you. my biggest fear is the black hole of paperwork and money to get these studies to the bedside. I am hoping geron can be the template for everyone else.
    Jhope,

    That is a good analogy. Black hole of spinal cord injury clinical trials. It takes a lot of work and there are many obstacles that must be overcome with each and every trial. With the network, we are systematically removing these obstacles for the clinicians and doing our best to encourage them to test the therapies they think will be effective but at the same time run rigorous clinical trials that are credible and convincing to other doctors.

    Chronic animal spinal cord injury studies are very labor-intensive and difficult to do. Over the past decade, we have held 4 workshops a year to teach laboratories how to do chronic rat spinal cord injury trials, how to take care of the animals, what must be done to expose their spinal cords later for transplantation or other therapies, and how to evaluate the animals. That has been our goal at the Keck Center for Collaborative Neuroscience. Each workshop has 10-12 participants. In addition to the four workshops a year, I also teach at other workshops and we take on students and postdocs. We have trained over 500 investigators.

    Now, as the treatment keep coming out of the pipeline, we need keep them out of the black holes and tested in human clinical trials.

    Wise.

  8. #8
    J Neurosci Res. 2008 Nov 1;86(14):3039-51.

    A technological platform to optimize combinatorial treatment design and discovery for chronic spinal cord injury.

    Guertin PA.

    Neuroscience Unit, Laval University Medical Center (CHUL-CHUQ), Quebec City, Quebec, Canada. Pierre.Guertin@crchul.ulaval.ca

    Chronic spinal cord injury (SCI) is associated with the development of serious medical concerns. In fact, it is increasingly well documented that most SCI patients who survive the first 24 hr will rapidly develop, within a few months to a few years, cardiovascular problems, type II diabetes, muscle wasting, osteoporosis, immune deficiencies, and other life-threatening problems. The cellular mechanisms underlying these so-called secondary health complications remain unclear, and no drug or standard approach has been developed to specifically treat these complications. To investigate the cellular and metabolic changes associated with chronic SCI and functional recovery, work mainly from our laboratory recently has led to the characterization of a mouse model of chronic paraplegia. This review reports cellular, systemic, and metabolic changes (associated mainly with secondary health complications) occurring within a few days to a few weeks after SCI in low-thoracic spinal cord-transected mice. We also describe our research platform developed to ease technological transfer and to accelerate drug-screening studies in animals. A global understanding of the many chronic changes occurring after SCI together with efficient tools and approaches for testing new or existing drug candidates is likely to yield the design of innovative treatments against secondary complications that combine cellular plasticity-modulating agents, locomotor network-activating drugs, hormonal therapy, and exercise training. (c) 2008 Wiley-Liss, Inc.


    http://www.ncbi.nlm.nih.gov/pubmed/1...ubmed_RVDocSum
    “As the cast of villains in SCI is vast and collaborative, so too must be the chorus of hero's that rise to meet them” Ramer et al 2005

  9. #9
    The message is that there are therapies that are making animals with chronic spinal cord injury walk. Some of these studies are still in their early phases but there is no question that it is possible and many of the therapies that are beneficial in acute and subacute injury also appear to be beneficial in chronic spinal cord injury.

    Chronic spinal cord injury studies are hard to do for several reasons. First, many researchers are pessimistic about restoring function in chronic spinal cord injury and it is very hard to get grants to study chronic spinal cord injury. Second, the research takes a long time, is labor-intensive, and difficult to do. You need a team of researchers and animal care technicians, behavioral analyeses, as well as willingness to do fastidious morphological analyses of the spinal cords. Few laboratories are equipped with resources to do such studies. Third, there is a lack of immune-compatible cell source of transplantation in rats.

    Fortunately, we just spent four years and developed the first isogenic strain of GFP (green-fluorescent protein) expressing Fischer rats that can be used to transplant cells into other Fischer rats without immune suppression. For many years, we have been developing and teaching people how to use the Impactor model of spinal cord injury for chronic spinal cord injury. Animal care protocols have been established. So, there will be many more chronic spinal cord injury studies in the coming years.

    Wise.

  10. #10
    Quote Originally Posted by Wise Young View Post
    • Dr. Davies presented some of his studies in Beijing and in Hong Kong. I am excited about the prospects of using decorin to treat spinal cord injury. However, I am unsure of his chronic spinal cord injury experiments and that is in part because he uses a hemisection model which is not particularly good for assessing behavior (since most chronic hemisected rats are walking almost normally). In my opinion, decorin needs to be tested in a chronic spinal cord contusion model. He told me that there will be more decorin available for other investigators in the coming months and our laboratory would be very interested in testing it.
    Wise.
    Dr.Young,

    I was just wondering, if you do test decorin and find it to benefit contusion modules, would this be something that could be added to the cord blood+lithium combo? The reason I ask this is because as you are not a fan of the glial 'scar' theory, would there be any point of adding this to your therapy as you have said the umbilical cord cells would be acting as a bridge to gives axons something to grow through the gap, so would it be used in combination with another therapy eventually, or have I gone of track and am wrong? Thanks.

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