researchblog

[kivi66]

Dr.Wise, thanks a lot and, don't consider as an impudence, dig a little bit also here: "Dr.Wise, how can you in reality know what can help spinal cord regeneration and functional restoration in human, if this goal has never been achieved even with lab rats. Or it has been achieved?"
Thanks for continuing to reply to me .

[Leif]

Originally Posted by kivi66

Dr.Wise, thanks a lot and, don't consider as an impudence, dig a little bit also here: "Dr.Wise, how can you in reality know what can help spinal cord regeneration and functional restoration in human, if this goal has never been achieved even with lab rats. Or it has been achieved?"
Thanks for continuing to reply to me .

Kivi - You are human? Then fix sci. Don't be a lazy butt!

[kivi66]

Leif, let's wait for Drs.Wise's and Silver's publications. For they are both definitely humans, it would be absolutely inhuman for their part after all their encouraging statements do not provide us with any weapon for doing away with this Abomination.
Dr.Wise, you have a chance to change your status from ordinary mortal to nephalem and herald the beginning of a New Era. The end of this year is a highly suitable crucial point for such mission, not a final victory, of corse, but some sign that the tunnel is not endless. ("D3" has the same principle as "Mafia" - attack and will be attacked, so, you know the rules).

[Wise Young]

Originally Posted by kivi66

Dr.Wise, thanks a lot and, don't consider as an impudence, dig a little bit also here: "Dr.Wise, how can you in reality know what can help spinal cord regeneration and functional restoration in human, if this goal has never been achieved even with lab rats. Or it has been achieved?"
Thanks for continuing to reply to me .

kivi66,

Spinal cord injury is being cured every day. Look at the people who have incomplete spinal cord injury. Look at a rat that has had half of its spinal cord cut. Within 6 months, most people with incomplete spinal cord injuries are able to walk so well that you wouldn't know that they were spinal injured. Likewise, a rat is able to walk almost normally within 6 weeks after two thirds of the spinal cord has been cut. I use to monitor the spinal cord of kids of tumors of the spinal cord. By the end of surgery, there could not have been more than 10% of the spinal cord remaining. Yet, most of these children walk out of the hospital.

The lesson from these observations is that you don't have to regrow all that much of the spinal cord to get function back. In fact, you just need to add enough axons to restore about 10% of axons and the person should behave like most incomplete spinal cord injuries and recover substantially. I hope that is what we are doing when we transplant umbilical cord blood mononuclear cells and treat them with lithium. Not everybody will recover but those with 10% of the axons in the spinal cord should recover.

Two decades of animal studies have shown us that axons can and do regrow in the spinal cord. Many axons probably regrow without any therapy. Most people with so called "complete" spinal cord injury will recover some function, often years after injury. These often appear as patches of sensation, ability to move a finger or a joint, recovery of temperature control and sweating, and deep sensations. Spasticity may increase or decrease. Likewise, neuropathic pain can come or go. These result from spontaneous changes of the spinal cord.

The animal studies have also shown that several obstacles block axonal growth. The first was Nogo, the myelin-associated protein that stops axonal growth. Animal studies show that antibodies against Nogo will stimulate some corticospinal axons to grow across the injury site. It also causes surviving axons to sprout and reconnect to more neurons. Chondroitinase seems to allow axons to grow across the injury site as well, especially when combined with lithium [1].

Lithium strongly stimulates axonal growth in rat spinal cords when given after spinal cord injury [2]. Lithium also stimulates umbilical cord blood mononuclear cells to proliferate and to produce neurotrophins known to stimulate axons growth [3]. Over two dozen laboratories have reported the human umbilical cord blood cells transplanted into the spinal cord, as late as 1-2 weeks after injury, will improve functional recovery after spinal cord injury. I have reviewed this literature in the past but several new papers have appeared in the past year supporting the beneficial effects of umbilical cord blood mononuclear cells [4-10].

We are testing the effects of umbilical cord blood mononuclear cells combined with lithium in people with chronic spinal cord injury. As I have indicated here, our phase 2 trials indicate that the treatments are safe and may be restoring function to some people. We are therefore progressing to phase 3 multicenter clinical trials to test the therapies in double-blind randomized and controlled trials. We are not saying that the therapy that we are testing is the only one. However, we believe that this is a safe and worthwhile therapy to test in phase 3. If it does not work, we will go forward to other therapies and continue testing until we find something that works.

Wise.


References Cited

1. Yick LW, So KF, Cheung PT and Wu WT (2004). Lithium chloride reinforces the regeneration-promoting effect of chondroitinase ABC on rubrospinal neurons after spinal cord injury. Journal of Neurotrauma 21: 932-43. Department of Anatomy, Faculty of Medicine, The University of Hong Kong, Hong Kong. After spinal cord injury, enzymatic digestion of chondroitin sulfate proteoglycans promotes axonal regeneration of central nervous system neurons across the lesion scar. We examined whether chondroitinase ABC (ChABC) promotes the axonal regeneration of rubrospinal tract (RST) neurons following injury to the spinal cord. The effect of a GSK-3beta inhibitor, lithium chloride (LiCl), on the regeneration of axotomized RST neurons was also assessed. Adult rats received a unilateral hemisection at the seventh cervical spinal cord segment (C7). Four weeks after different treatments, regeneration of RST axons across the lesion scar was examined by injection of Fluoro-Gold at spinal segment T2, and locomotor recovery was studied by a test of forelimb usage. Injured RST axons did not regenerate spontaneously after spinal cord injury, and intraperitoneal injection of LiCl alone did not promote the regeneration of RST axons. Administration of ChABC at the lesion site enhanced the regeneration of RST axons by 20%. Combined treatment of LiCl together with ChABC significantly increased the regeneration of RST axons to 42%. Animals receiving combined treatment used both forelimbs together more often than animals that received sham or single treatment. Immunoblotting and immunohistochemical analysis revealed that LiCl induced the expression of inactive GSK-3beta as well as the upregulation of Bcl-2 in injured RST neurons. These results indicate that in vivo, LiCl inhibits GSK-3beta and reinforces the regeneration-promoting function of ChABC through a Bcl-2-dependent mechanism. Combined use of LiCl together with ChABC could be a novel treatment for spinal cord injury.

2. Dill J, Wang H, Zhou F and Li S (2008). Inactivation of glycogen synthase kinase 3 promotes axonal growth and recovery in the CNS. J Neurosci 28: 8914-28. Department of Neurology and Neuroscience Graduate Program, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8813, USA. Axonal regeneration is minimal after CNS injuries in adult mammals and medical treatments to recover neurological deficits caused by axon disconnection are extremely limited. The failure of axonal elongation is principally attributed to the nonpermissive environment and reduced intrinsic growth capacity. In this report, we studied the role of glycogen synthase kinase-3 (GSK-3) inactivation on neurite and axon growth from adult neurons via combined in vitro and in vivo approaches. We found that the major CNS inhibiting substrates including chondroitin sulfate proteoglycans could inactivate protein kinase B (Akt) and activate GSK-3beta signals in neurons. GSK-3 inactivation with pharmacologic inhibitors enhances neurite outgrowth of dorsal root ganglion neurons derived from adult mice or cerebellar granule neurons from postnatal rodents cultured on CNS inhibitors. Application of GSK-3 inhibitors stimulates axon formation and elongation of mature neurons whether in presence or absence of inhibitory substrates. Systemic application of the GSK-3 inhibitor lithium to spinal cord-lesioned rats suppresses the activity of this kinase around lesion. Treatments with GSK-3 inhibitors including a clinical dose of lithium to rats with thoracic spinal cord transection or contusion injuries induce significant descending corticospinal and serotonergic axon sprouting in caudal spinal cord and promote locomotor functional recovery. Our studies suggest that GSK-3 signal is an important therapeutic target for promoting functional recovery of adult CNS injuries and that administration of GSK-3 inhibitors may facilitate the development of an effective treatment to white matter injuries including spinal cord trauma given the wide use of lithium in humans.

3. Sun D and Young W (2008). Lithium stimulation of cord blood stem cell proliferation and growth factor production. WO/2008/055224. The present invention provides methods for expanding human umbilical cord blood stem cells and methods for stimulating growth factor production by cord blood stem cells using an in vitro cell culture system comprising a lithium salt. The present invention also provides in vivo methods for enhancing the survival and growth of transplanted cord blood stem cells by treating the cells with a lithium salt prior to transplantation. In vivo methods for reducing rejection of transplanted cord blood stem cells by administering a lithium salt after transplantation are also provided.

4. Schira J, Gasis M, Estrada V, Hendricks M, Schmitz C, Trapp T, Kruse F, Kogler G, Wernet P, Hartung HP and Muller HW (2012). Significant clinical, neuropathological and behavioural recovery from acute spinal cord trauma by transplantation of a well-defined somatic stem cell from human umbilical cord blood. Brain : a journal of neurology 135: 431-46. Molecular Neurobiology Laboratory, Department of Neurology, Heinrich-Heine-University Medical Centre Dusseldorf, Moorenstr. 5, 40223 Dusseldorf, Germany. Stem cell therapy is a potential treatment for spinal cord injury and different stem cell types have been grafted into animal models and humans suffering from spinal trauma. Due to inconsistent results, it is still an important and clinically relevant question which stem cell type will prove to be therapeutically effective. Thus far, stem cells of human sources grafted into spinal cord mostly included barely defined heterogeneous mesenchymal stem cell populations derived from bone marrow or umbilical cord blood. Here, we have transplanted a well-defined unrestricted somatic stem cell isolated from human umbilical cord blood into an acute traumatic spinal cord injury of adult immune suppressed rat. Grafting of unrestricted somatic stem cells into the vicinity of a dorsal hemisection injury at thoracic level eight resulted in hepatocyte growth factor-directed migration and accumulation within the lesion area, reduction in lesion size and augmented tissue sparing, enhanced axon regrowth and significant functional locomotor improvement as revealed by three behavioural tasks (open field Basso-Beattie-Bresnahan locomotor score, horizontal ladder walking test and CatWalk gait analysis). To accomplish the beneficial effects, neither neural differentiation nor long-lasting persistence of the grafted human stem cells appears to be required. The secretion of neurite outgrowth-promoting factors in vitro further suggests a paracrine function of unrestricted somatic stem cells in spinal cord injury. Given the highly supportive functional characteristics in spinal cord injury, production in virtually unlimited quantities at GMP grade and lack of ethical concerns, unrestricted somatic stem cells appear to be a highly suitable human stem cell source for clinical application in central nervous system injuries.

5. Rodrigues LP, Iglesias D, Nicola FC, Steffens D, Valentim L, Witczak A, Zanatta G, Achaval M, Pranke P and Netto CA (2012). Transplantation of mononuclear cells from human umbilical cord blood promotes functional recovery after traumatic spinal cord injury in Wistar rats. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.] 45: 49-57. Programa de Pos-Graduacao em Neurociencias, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil. lpro@terra.com.br. Cell transplantation is a promising experimental treatment for spinal cord injury. The aim of the present study was to evaluate the efficacy of mononuclear cells from human umbilical cord blood in promoting functional recovery when transplanted after a contusion spinal cord injury. Female Wistar rats (12 weeks old) were submitted to spinal injury with a MASCIS impactor and divided into 4 groups: control, surgical control, spinal cord injury, and one cell-treated lesion group. Mononuclear cells from umbilical cord blood of human male neonates were transplanted in two experiments: a) 1 h after surgery, into the injury site at a concentration of 5 x 10(6) cells diluted in 10 microL 0.9% NaCl (N = 8-10 per group); b) into the cisterna magna, 9 days after lesion at a concentration of 5 x 10(6) cells diluted in 150 microL 0.9% NaCl (N = 12-14 per group). The transplanted animals were immunosuppressed with cyclosporin-A (10 mg/kg per day). The BBB scale was used to evaluate motor behavior and the injury site was analyzed with immunofluorescent markers to label human transplanted cells, oligodendrocytes, neurons, and astrocytes. Spinal cord injury rats had 25% loss of cord tissue and cell treatment did not affect lesion extension. Transplanted cells survived in the injured area for 6 weeks after the procedure and both transplanted groups showed better motor recovery than the untreated ones (P < 0.05). The transplantation of mononuclear cells from human umbilical cord blood promoted functional recovery with no evidence of cell differentiation.

6. Park SI, Lim JY, Jeong CH, Kim SM, Jun JA, Jeun SS and Oh WI (2012). Human umbilical cord blood-derived mesenchymal stem cell therapy promotes functional recovery of contused rat spinal cord through enhancement of endogenous cell proliferation and oligogenesis. Journal of biomedicine & biotechnology 2012: 362473. Institute of Catholic Integrative Medicine (ICIM), Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Republic of Korea. Numerous studies have shown the benefits of mesenchymal stem cells (MSCs) on the repair of spinal cord injury (SCI) model and on behavioral improvement, but the underlying mechanisms remain unclear. In this study, to investigate possible mechanisms by which MSCs contribute to the alleviation of neurologic deficits, we examined the potential effect of human umbilical cord blood-derived MSCs (hUCB-MSCs) on the endogenous cell proliferation and oligogenesis after SCI. SCI was injured by contusion using a weight-drop impactor and hUCB-MSCs were transplanted into the boundary zone of the injured site. Animals received a daily injection of bromodeoxyuridine (BrdU) for 7 days after treatment to identity newly synthesized cells of ependymal and periependymal cells that immunohistochemically resembled stem/progenitor cells was evident. Behavior analysis revealed that locomotor functions of hUCB-MSCs group were restored significantly and the cavity volume was smaller in the MSCs-transplanted rats compared to the control group. In MSCs-transplanted group, TUNEL-positive cells were decreased and BrdU-positive cells were significantly increased rats compared with control group. In addition, more of BrdU-positive cells expressed neural stem/progenitor cell nestin and oligo-lineage cell such as NG2, CNPase, MBP and glial fibrillary acidic protein typical of astrocytes in the MSC-transplanted rats. Thus, endogenous cell proliferation and oligogenesis contribute to MSC-promoted functional recovery following SCI.

7. Park SS, Byeon YE, Ryu HH, Kang BJ, Kim Y, Kim WH, Kang KS, Han HJ and Kweon OK (2011). Comparison of canine umbilical cord blood-derived mesenchymal stem cell transplantation times: Involvement of astrogliosis, inflammation, intracellular actin cytoskeleton pathways, and neurotrophin. Cell Transplant Department of Veterinary Surgery, Laboratory of Stem cell and Tumor Biology, Department of Veterinary Public Health, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea, ohkweon@snu.ac.kr. Canine mesenchymal stem cells (cMSCs) derived from umbilical cord blood represent a potentially useful source of stem cells for therapy. The aim of this study was to compare the effects of different transplantation times of cMSCs after spinal cord injury (SCI). A total of 21 dogs were subjected to SCI by balloon-induced compression of the first lumbar vertebrae for 12 hrs. Of the 21 dogs, 12 were divided into four groups of three according to the time of stem cell (1X10(6)) transplantation at the injury site: control no treatment, 12 hr, 1 wk, and 2 wk. The remaining 9 animals were negative harvest (HA) time controls for each treatment group (n =3). Olby and Tarlov scores were used to evaluate functional recovery of the hind limbs. Markers for neuronal regeneration (Tuj-1, nestin, MAP2, and NF-M), astrogliosis (GALC, GFAP, and pSTAT3), signal molecules for actin cytoskeleton (RhoA, Cdc42, and Rac1), inflammation (COX-2), and neurotrophins (NT-3) were evaluated by Western blot analysis. Scores of the 1 wk transplantation group showed significant improvement compared to controls. Hematoxylin and eosin (H & E) staining revealed less fibrosis at the injury site in the 1wk transplantation group compared to other groups and immunohistochemistry showed increased expression of neuronal markers. Furthermore, in both 1 wk and 2 wk transplantation groups, Tuj-1, nestin, MAP2, NF-M, NT-3, and GFAP increased, but pSTAT3, GALC, and COX2 decreased. RhoA decreased and Rac1 and Cdc42 increased in the 1 wk transplantation group. In conclusion, transplantation of cMSCs one week after SCI was more effective in improving clinical signs and neuronal regeneration and reducing fibrosis formation compared to the other transplantation times evaluated. Subsequently, these data may contribute to the optimization of timing for MSC transplantation used as a therapeutic modality.

8. Park DH, Lee JH, Borlongan CV, Sanberg PR, Chung YG and Cho TH (2011). Transplantation of umbilical cord blood stem cells for treating spinal cord injury. Stem Cell Rev 7: 181-94. Department of Neurosurgery, Korea University Medical Center, Anam Hospital, Korea University College of Medicine, #126, 5-GA, Anam-Dong, Sungbuk-Ku, Seoul 136-705, Korea. doctorns@korea.com. Spinal cord injury (SCI) develops primary and secondary damage to neural tissue and this often results in permanent disability of the motor and sensory functions. However, there is currently no effective treatment except methylprednisolone, and the use of methylprednisolone has also been questioned due to its moderate efficacy and the drug's downside. Regenerative medicine has remarkably developed since the discovery of stem cells, and many studies have suggested the potential of cell-based therapies for neural injury. Especially, the therapeutic potential of human umbilical cord blood cells (hUCB cells) for intractable neurological disorders has been demonstrated using in vitro and vivo models. The hUCB cells are immune naive and they are able to differentiate into other phenotypes, including the neural lineage. Their ability to produce several neurotropic factors and to modulate immune and inflammatory reactions has also been noted. Recent evidence has emerged suggesting alternative pathways of graft-mediated neural repair that involve neurotrophic effects. These effects are caused by the release of various growth factors that promote cell survival, angiogenesis and anti-inflammation, and this is all aside from a cell replacement mechanism. In this review, we present the recent findings on the stemness properties and the therapeutic potential of hUCB as a safe, feasible and effective cellular source for transplantation in SCI. These multifaceted protective and restorative effects from hUCB grafts may be interdependent and they act in harmony to promote therapeutic benefits for SCI. Nevertheless, clinical studies with hUCB are still rare because of the concerns about safety and efficiency. Among these concerns, the major histocompatibility in allogeneic transplantation is an important issue to be addressed in future clinical trials for treating SCI.

9. Lee JH, Chung WH, Kang EH, Chung DJ, Choi CB, Chang HS, Hwang SH, Han H, Choe BY and Kim HY (2011). Schwann cell-like remyelination following transplantation of human umbilical cord blood (hUCB)-derived mesenchymal stem cells in dogs with acute spinal cord injury. J Neurol Sci 300: 86-96. Department of Veterinary Surgery, College of Veterinary Medicine, Konkuk University, Seoul, 143-701, Republic of Korea. Human umbilical cord blood derived mesenchymal stem cells (hUCB-MSCs) have significant therapeutic potential in cell-based therapies following spinal cord injury (SCI). To evaluate this potential, we conducted our preliminary investigations on the remyelination of injured spinal cords with hUCB-MSC transplantations and we observed its long term effects on dogs with SCI. Of the ten injured dogs, seven were transplanted with hUCB-MSCs 1 week after SCI, whereas the remaining three dogs were not transplanted. Two transplanted dogs died over the first month after transplantation because of urinary tract infection, bedsores and sepsis. The SCI dogs showed no improvement in motor and sensory functions and their urinary dysfunction persisted until they were euthanized (from 3 months to 1 year) while hind-limb recovery in 4 dogs among the five transplanted dogs was significantly improved. In the recovered dogs, functional recovery was sustained for three years following transplantation. Histological results from five transplanted dogs showed that many axons were remyelinated by P0-positive myelin sheaths after transplantation. Our results suggest that transplantation of hUCB-derived MSCs may have beneficial therapeutic effects. Furthermore, histological results provided the first in vivo evidence that hUCB-MSCs are able to enhance the remyelination of peripheral-type myelin sheaths following SCI.

10. Deng XY, Zhou RP, Lu KW and Jin DD (2010). [Lithium chloride combined with human umbilical cord blood mesenchymal stem cell transplantation for treatment of spinal cord injury in rats]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 30: 2436-9. Department of Spinal Surgery, Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China. dengxuyong@tom.com. OBJECTIVE: To observe the effects of lithium chloride combined with human umbilical cord blood mesenchymal stem cell (hUCB-SCs) transplantation in the treatment of spinal cord injury in rats. METHODS: Eighty female SD rats with complete T9 spinal cord transaction were randomized into 4 groups (n=20), namely the control group (group A), lithium chloride group (group B), hUCB-SCs group (group C) and hUCB-SCs(+) lithium chloride group (group D). On days 1 and 3 and the last days of the following weeks postoperatively, the motor function of the hindlimb of the rats were evaluated according to the BBB scores. At 8 weeks, all the rats were sacrificed and the spinal cords were taken for morphological observation. The spinal cord tissues at the injury site were observed with Brdu nuclear labeling to identify the survival and migration of the transplanted SCs. The regeneration and distribution of the spinal nerve fibers were observed with fluorescent-gold (FG) spinal cord retrograde tracing. RESULTS: Brdu labeling showed that the transplanted hUCB-SCs survived and migrated in the spinal cord 8 weeks postoperatively in groups C and D. FG retrograde tracing identified a small amount of pyramidal cells that migrated across the injury site in groups C and D. The BBB scores of the hindlimb motor function 8 weeks postoperatively were 4.11-/+0.14, 4.50-/+0.15, 8.31-/+0.11 and 11.15-/+0.18 in groups A, B, C and D, respectively. CONCLUSION: Lithium chloride can promote the survival and differentiation of hUCB-SCs into neural cells at the injury site. Lithium chloride combined with hUCB-SCs transplantation may accelerate functional recovery of the hindlimbs in rats with complete transection of the spinal cord.

[paolocipolla]

Originally Posted by Wise Young

kivi66,

Spinal cord injury is being cured every day.
...

Really? Why are we all sitting then? I think there is no cure yet... unless I have missed something big...

Paolo

[Christin L]

Originally Posted by Wise Young

kivi66,

Spinal cord injury is being cured every day. Look at the people who have incomplete spinal cord injury. Look at a rat that has had half of its spinal cord cut. Within 6 months, most people with incomplete spinal cord injuries are able to walk so well that you wouldn't know that they were spinal injured.

Please Dr Young, you can´t mean this! I haven´t heard of any incomplete person who can walk as if they haven´t been injured. Please tell me what to do to get that well. I am incomplete C5 and I managed to walk after 6 months, but extremely slow, short distances and with support. And everything else is completely damaged, too.

I follow your work intensively and really hope that your methods will be successful, soon. But there is no cure today that I know of, and I hope that some miraculous cure will come now, not as far as in 5 years. We´re desperate! At least I am.

Christin

[kivi66]

"Spinal cord injury is being cured every day. Look at the people who have incomplete spinal cord injury. Look at a rat that has had half of its spinal cord cut. Within 6 months, most people with incomplete spinal cord injuries are able to walk so well that you wouldn't know that they were spinal injured."
Dr.Wise, it is called "substitution of concepts". Things, you are talking about, are natural healing with supportive therapy (Methylprednisolone at alias, you know), but not a Cure.

[lakboy]

I think Dr Wise means patients who are pronounced ASIA D at the time of injury or soon after, I am ASIA B and I don't walk , and I personally know at least 40 people who are ASIA C and they too don't walk inspite of intensive physical therapy.

[khmorgan]

Originally Posted by paolocipolla

Really? Why are we all sitting then? I think there is no cure yet... unless I have missed something big...

Oh, common guys, read what he says, not what you want him to say. He never said all spinal cord injuries are being cured every day. When you hear that breast cancer is being cured everyday, do you scream "Lies, lies!"?

What a reasonable person gets from what he said is that more and more SCIs leave the hospital walking everyday. Unfortunately, the ones who were cured are not here reading this forum and agreeing with him. I'll bet that if you were cured. you wouldn't be either.

[paolocipolla]

Originally Posted by kivi66

"Spinal cord injury is being cured every day. Look at the people who have incomplete spinal cord injury. Look at a rat that has had half of its spinal cord cut. Within 6 months, most people with incomplete spinal cord injuries are able to walk so well that you wouldn't know that they were spinal injured."
Dr.Wise, it is called "substitution of concepts". Things, you are talking about, are natural healing with supportive therapy (Methylprednisolone at alias, you know), but not a Cure.

Thanks Kivi for mentioning "substitution of concepts" I didn't know about it, but I see it is a well known instructional strategy for promoting conceptual change
http://www.springerlink.com/content/d6j65813k2458527/