This is an extremely impressive discovery. To have peripheral axons/nerves capable of self guided regeneration all the way back to their original source of function through the maze of other surrounding axons/nerves with in the spinal cord is one of the largest obstacles that I feared might not be resolvable. Amazing stuff.
http://sackler.tufts.edu/Faculty-and-Re ... light.aspx
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New Approaches to Spinal Cord Regeneration
Spinal cord injury has devastating consequences for its many victims and their communities. When even a small region of the spinal cord is damaged, the flow of information through that region is impaired. As a result, sensory information coming from below the injury cannot reach the brain, and command signals from the brain cannot reach lower regions of the spinal cord. Damage in the thoracic region of the cord, for example, effectively cuts off communication between the brain and the entire lower half of the body. Unfortunately, nerve fibers within the central nervous system, which includes the spinal cord, are unable to regrow (regenerate) after they are damaged. A surgical papyrus, written over 4000 years ago, noted “One having a crushed vertebra in his neck; he is unconscious of his two arms, his two legs, he is speechless. An ailment not to be treated." Today, the prognosis for recovery from spinal injuries is still poor.
Pamela Harvey, a Neuroscience graduate student in Eric Frank’s laboratory in the Department of Physiology, has been investigating methods for stimulating damaged axons to regenerate within the spinal cord. She has been studying a particular class of spinal injuries, called brachial plexus injuries, which often result from motor vehicle accidents or falls. In these injuries, the nerves leading from the arm into the spinal cord are broken or damaged, causing loss of sensory and/or motor function of the arms. Sensory nerve axons can grow within the peripheral nerves themselves, but further growth is thwarted once the nerve fibers reach the cord. Just as for nerve fibers damaged within the cord itself, regenerating sensory axons are unable to grow into the spinal cord and re-establish their synaptic connections with other neurons that are necessary to restore sensory function.
One reason that the regeneration of nerve fibers within the cord is so poor is that the proteins present during development that promote nerve growth are not present in adults. Injection of several of these neurotrophic factors into rats with damaged sensory nerves does promote some regeneration of sensory fibers back into the cord. Pam has found that one factor in particular, artemin, is especially effective in stimulating robust regeneration. Not only do the nerve fibers grow back into the cord, but they also re-establish functional connections with their target neurons. These connections are sufficient to restore near-normal use of the arm.
Pam finds that this regeneration is remarkably specific. Sensory axons innervating a small patch of skin regenerate back to the same location in the spinal cord that they occupied before the injury. Similarly, muscle sensory axons, which normally project to deeper spinal layers, also project to deeper layers after regeneration. These surprising results suggest that molecular cues capable of directing the growth of regenerating axons to their targets are present in the adult, mammalian spinal cord. The implication is that these and other cues may also be available to guide the regeneration of other classes of spinal axons, such as those damaged in other types of spinal injuries. If so, it may be possible to develop generalized strategies for promoting specific regeneration of these axons as well.
http://www.ncbi.nlm.nih.gov/pubmed/1943 ... d_RVDocSum
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Blockade of Nogo receptor ligands promotes functional regeneration of sensory axons after dorsal root crush.
Harvey PA, Lee DH, Qian F, Weinreb PH, Frank E.
Department of Physiology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
A major impediment for regeneration of axons within the CNS is the presence of multiple inhibitory factors associated with myelin. Three of these factors bind to the Nogo receptor, NgR, which is expressed on axons. Administration of exogenous blockers of NgR or NgR ligands promotes the regeneration of descending axonal projections after spinal cord hemisection. A more detailed analysis of CNS regeneration can be made by examining the growth of specific classes of sensory axons into the spinal cord after dorsal root crush injury. In this study, we assessed whether administration of a soluble peptide fragment of the NgR (sNgR) that binds to and blocks all three NgR ligands can promote regeneration after brachial dorsal root crush in adult rats. Intraventricular infusion of sNgR for 1 month results in extensive regrowth of myelinated sensory axons into the white and gray matter of the dorsal spinal cord, but unmyelinated sensory afferents do not regenerate. In concert with the anatomical growth of sensory axons into the cord, there is a gradual restoration of synaptic function in the denervated region, as revealed by extracellular microelectrode recordings from the spinal gray matter in response to stimulation of peripheral nerves. These positive synaptic responses are correlated with substantial improvements in use of the forelimb, as assessed by paw preference, paw withdrawal to tactile stimuli and the ability to grasp. These results suggest that sNgR may be a potential therapy for restoring sensory function after injuries to sensory roots.
New Approaches to Spinal Cord Regeneration
-
Christopher
- Posts: 845
- Joined: Wed Jun 18, 2003 10:09 pm
- Injury Description, Date, extent, surgical intervention etc: Date of Injury: 12/15/02
Level of Injury:
-dominant side C5, C6, & C7 avulsed. C8 & T1 stretched & crushed
BPI Related Surgeries:
-2 Intercostal nerves grafted to Biceps muscle,
-Free-Gracilis muscle transfer to Biceps Region innervated with 2 Intercostal nerves grafts.
-2 Sural nerves harvested from both Calves for nerve grafting.
-Partial Ulnar nerve grafted to Long Triceps.
-Uninjured C7 Hemi-Contralateral cross-over to Deltoid muscle.
-Wrist flexor tendon transfer to middle, ring, & pinky finger extensors.
Surgical medical facility:
Brachial Plexus Clinic at The Mayo Clinic, Rochester MN
(all surgeries successful)
"Do what you can, with what you have, where you are."
~Theodore Roosevelt - Location: Los Angeles, California USA
-
Chillywil91
- Posts: 17
- Joined: Tue Feb 10, 2009 2:25 pm
Re: New Approaches to Spinal Cord Regeneration
So when will they begin clinical trials on humans?
-
Christopher
- Posts: 845
- Joined: Wed Jun 18, 2003 10:09 pm
- Injury Description, Date, extent, surgical intervention etc: Date of Injury: 12/15/02
Level of Injury:
-dominant side C5, C6, & C7 avulsed. C8 & T1 stretched & crushed
BPI Related Surgeries:
-2 Intercostal nerves grafted to Biceps muscle,
-Free-Gracilis muscle transfer to Biceps Region innervated with 2 Intercostal nerves grafts.
-2 Sural nerves harvested from both Calves for nerve grafting.
-Partial Ulnar nerve grafted to Long Triceps.
-Uninjured C7 Hemi-Contralateral cross-over to Deltoid muscle.
-Wrist flexor tendon transfer to middle, ring, & pinky finger extensors.
Surgical medical facility:
Brachial Plexus Clinic at The Mayo Clinic, Rochester MN
(all surgeries successful)
"Do what you can, with what you have, where you are."
~Theodore Roosevelt - Location: Los Angeles, California USA
Re: New Approaches to Spinal Cord Regeneration
Don't know when trials would begin. I can guarantee you this, that they'll need lots of funding (money)! Awareness and fund raising should be our top priorities as a group, or we'll never see a cure in our lifetimes...
http://www.eurekalert.org/pub_releases/ ... 072809.php#
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2-Aug-2009
Finding the right connection after spinal cord injury
IMAGE: This image shows a target cell in the brain (green) contacted by an axon (red) regenerating into the brain from the spinal cord.
In a major step in spinal cord injury research, scientists at the University of California, San Diego School of Medicine have demonstrated that regenerating axons can be guided to their correct targets and re-form connections after spinal cord injury. Their findings will be published in the advance online edition of the journal Nature Neuroscience on August 2.
In the last few years, researchers have shown that the severed wires of the spinal cord, called axons, can be induced to regenerate into and beyond sites of experimental spinal cord injury. But a key question has been how these regenerating axons, on reaching the end of an injury site, can be guided to a correct cell target when faced with millions of potential targets. Further, can regenerating axons form functional, electrical connections called synapses?
"The ability to guide regenerating axons to a correct target after spinal cord injury has always been a point of crucial importance in contemplating translation of regeneration therapies to humans," said senior author Mark Tuszynski, MD, PhD, professor of neurosciences and director of the Center for Neural Repair at UC San Diego, and neurologist at the Veterans Affairs San Diego Health System. "While our findings are very encouraging in this respect, they also highlight the complexity of restoring function in the injured spinal cord."
The UC San Diego study looked at regenerating sensory axons in rat models of spinal cord injury. Sensory systems of the body send axons – long, slender projections of the neuron – into the spinal cord to convey information regarding touch, position, and pain. Many sensory axons are covered by an insulating myelin sheath which helps these impulses travel efficiently to the brain.
In certain spinal cord injuries, the axons are severed and the myelin sheath damaged. Loss of these systems results in an inability to feel or sense the body. The axons can no longer link to their targets in the brain, which blocks the electrical impulses from reaching the central nervous system.
The UC San Diego scientists showed that regenerating axons can be guided to correct targets using a type of chemical hormone called a growth factor. The team utilized a type of chemical hormone, a nervous system growth factor called neurotrophin-3 (NT-3), to guide regenerating sensory axons to the appropriate target and support synapse formation. Regeneration required two other treatments at the same time: placing a cell bridge in the spinal cord injury site to support axon growth, and a "conditioning" stimulus to the injured neuron that turned on regeneration genes for new growth.
When the growth factor was placed in the correct target as a guidance cue, axons regenerated into it and formed synapses. When the growth factor was placed in the wrong target, axons also followed the growth factor and grew into the wrong region.
Using high-resolution imaging systems, the scientists showed that regenerating axons guided to the correct cell formed synapses that were precisely on target. These axons contained rounded vesicles – small packets at the end of the axon, packed with the chemical messengers needed to support electrical activity in the newly formed circuit.
Nonetheless, the connections were not electrically active. Additional study revealed the likely reason for this: the regenerating axons were not covered in myelin, the insulating material of the nervous system.
"Restoring axonal circuitry is complex, requiring several concurrent therapies to achieve axonal regeneration into and beyond a spinal cord lesion site," said Tuszynski. "But, just as an electrical circuit needs insulation so it doesn't short-circuit, it appears that these regenerating axons require restoration of the myelin sheath to ultimately restore function." This will be the next step in the team's research.
In earlier research (reported in PNAS April 6), the UC San Diego team achieved the first corticospinal motor axon regeneration by genetically engineering injured neurons to over-express receptors for another type of nervous system growth factor called brain-derived neurotrophic factor (BDNF). The growth factor was delivered to a brain lesion site in injured rats, where axons responded and regenerated into the injury site.
###
The lead author of the Nature Neuroscience study is Laura Taylor Alto of UCSD's Department of Neurosciences. Additional contributors include Leif A. Havton of UCLA, and James M. Conner, Edmund R. Hollis II and Armin Blesch of UCSD Department of Neurosciences. Their work was supported by the National Institutes of Health, the Veterans Administration, the International Spinal Research Trust, Wings for Life, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the Bernard and Anne Spitzer Charitable Trust.
Contact: Debra Kain
ddkain@ucsd.edu
619-543-6163
University of California - San Diego
http://www.eurekalert.org/pub_releases/ ... 072809.php#
================================================
2-Aug-2009
Finding the right connection after spinal cord injury
IMAGE: This image shows a target cell in the brain (green) contacted by an axon (red) regenerating into the brain from the spinal cord.
In a major step in spinal cord injury research, scientists at the University of California, San Diego School of Medicine have demonstrated that regenerating axons can be guided to their correct targets and re-form connections after spinal cord injury. Their findings will be published in the advance online edition of the journal Nature Neuroscience on August 2.
In the last few years, researchers have shown that the severed wires of the spinal cord, called axons, can be induced to regenerate into and beyond sites of experimental spinal cord injury. But a key question has been how these regenerating axons, on reaching the end of an injury site, can be guided to a correct cell target when faced with millions of potential targets. Further, can regenerating axons form functional, electrical connections called synapses?
"The ability to guide regenerating axons to a correct target after spinal cord injury has always been a point of crucial importance in contemplating translation of regeneration therapies to humans," said senior author Mark Tuszynski, MD, PhD, professor of neurosciences and director of the Center for Neural Repair at UC San Diego, and neurologist at the Veterans Affairs San Diego Health System. "While our findings are very encouraging in this respect, they also highlight the complexity of restoring function in the injured spinal cord."
The UC San Diego study looked at regenerating sensory axons in rat models of spinal cord injury. Sensory systems of the body send axons – long, slender projections of the neuron – into the spinal cord to convey information regarding touch, position, and pain. Many sensory axons are covered by an insulating myelin sheath which helps these impulses travel efficiently to the brain.
In certain spinal cord injuries, the axons are severed and the myelin sheath damaged. Loss of these systems results in an inability to feel or sense the body. The axons can no longer link to their targets in the brain, which blocks the electrical impulses from reaching the central nervous system.
The UC San Diego scientists showed that regenerating axons can be guided to correct targets using a type of chemical hormone called a growth factor. The team utilized a type of chemical hormone, a nervous system growth factor called neurotrophin-3 (NT-3), to guide regenerating sensory axons to the appropriate target and support synapse formation. Regeneration required two other treatments at the same time: placing a cell bridge in the spinal cord injury site to support axon growth, and a "conditioning" stimulus to the injured neuron that turned on regeneration genes for new growth.
When the growth factor was placed in the correct target as a guidance cue, axons regenerated into it and formed synapses. When the growth factor was placed in the wrong target, axons also followed the growth factor and grew into the wrong region.
Using high-resolution imaging systems, the scientists showed that regenerating axons guided to the correct cell formed synapses that were precisely on target. These axons contained rounded vesicles – small packets at the end of the axon, packed with the chemical messengers needed to support electrical activity in the newly formed circuit.
Nonetheless, the connections were not electrically active. Additional study revealed the likely reason for this: the regenerating axons were not covered in myelin, the insulating material of the nervous system.
"Restoring axonal circuitry is complex, requiring several concurrent therapies to achieve axonal regeneration into and beyond a spinal cord lesion site," said Tuszynski. "But, just as an electrical circuit needs insulation so it doesn't short-circuit, it appears that these regenerating axons require restoration of the myelin sheath to ultimately restore function." This will be the next step in the team's research.
In earlier research (reported in PNAS April 6), the UC San Diego team achieved the first corticospinal motor axon regeneration by genetically engineering injured neurons to over-express receptors for another type of nervous system growth factor called brain-derived neurotrophic factor (BDNF). The growth factor was delivered to a brain lesion site in injured rats, where axons responded and regenerated into the injury site.
###
The lead author of the Nature Neuroscience study is Laura Taylor Alto of UCSD's Department of Neurosciences. Additional contributors include Leif A. Havton of UCLA, and James M. Conner, Edmund R. Hollis II and Armin Blesch of UCSD Department of Neurosciences. Their work was supported by the National Institutes of Health, the Veterans Administration, the International Spinal Research Trust, Wings for Life, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the Bernard and Anne Spitzer Charitable Trust.
Contact: Debra Kain
ddkain@ucsd.edu
619-543-6163
University of California - San Diego
-
MW
- Posts: 81
- Joined: Fri Jun 19, 2009 6:13 pm
- Injury Description, Date, extent, surgical intervention etc: LTBPI, Feb 2009, hit by truck while on a run. Free muscle transfer at Mayo Clinic 6 months later.
- Location: Chicago, IL
Re: New Approaches to Spinal Cord Regeneration
With respect to the Tufts study, I sent an email to the authors telling them I really appreciated their work and I hoped for human testing soon. They said that they were encouraged that their work may eventually help BPI patients but it's still a long way off. Currently their work has focused on BP crush injuries and repairing them soon after, so they need to work on avulsion injuries, and repairing them long after the injury (at least in my case). I've pasted part of their response to me below:
***
Thanks for your very supportive note. I only wish we were closer to something that would be of use for people like yourself rather than rats. You might have seen an article in Nature Neuroscience in April, 2008, by Wang et al (Frank Porreca was the corresponding author, we were middle authors) showing that the neurotrophic factor artemin was also very effecting in restoring sensory function after crush injuries of the brachial dorsal roots in rats. We have now gone on with that work to show that the sensory nerve connections in the spinal cord re-established by artemin treatment are specific, in the sense that the nerve fibers grow back to their correct locations in the cord. We have submitted that work for publication, and I will let you know when it is published.
Two major tasks now are to get regeneration to occur when the sensory roots are actually broken (avulsed, like yours) rather than crushed and to get regeneration to occur after a delay, rather than treating with artemin right away. On the first point, we have had some success in gluing the roots back in place onto the cord with a biological glue used by the body in making clots (fibrin), but the results are variable and we don't yet know why. On the second point, we (and Frank Porreca) have been successful in getting some regeneration even if delaying treatment for 3 days after crush, but obviously we need something that works long after the injury to provide help for people who have already sustained these injuries.
***
Thanks for your very supportive note. I only wish we were closer to something that would be of use for people like yourself rather than rats. You might have seen an article in Nature Neuroscience in April, 2008, by Wang et al (Frank Porreca was the corresponding author, we were middle authors) showing that the neurotrophic factor artemin was also very effecting in restoring sensory function after crush injuries of the brachial dorsal roots in rats. We have now gone on with that work to show that the sensory nerve connections in the spinal cord re-established by artemin treatment are specific, in the sense that the nerve fibers grow back to their correct locations in the cord. We have submitted that work for publication, and I will let you know when it is published.
Two major tasks now are to get regeneration to occur when the sensory roots are actually broken (avulsed, like yours) rather than crushed and to get regeneration to occur after a delay, rather than treating with artemin right away. On the first point, we have had some success in gluing the roots back in place onto the cord with a biological glue used by the body in making clots (fibrin), but the results are variable and we don't yet know why. On the second point, we (and Frank Porreca) have been successful in getting some regeneration even if delaying treatment for 3 days after crush, but obviously we need something that works long after the injury to provide help for people who have already sustained these injuries.
-
Christopher
- Posts: 845
- Joined: Wed Jun 18, 2003 10:09 pm
- Injury Description, Date, extent, surgical intervention etc: Date of Injury: 12/15/02
Level of Injury:
-dominant side C5, C6, & C7 avulsed. C8 & T1 stretched & crushed
BPI Related Surgeries:
-2 Intercostal nerves grafted to Biceps muscle,
-Free-Gracilis muscle transfer to Biceps Region innervated with 2 Intercostal nerves grafts.
-2 Sural nerves harvested from both Calves for nerve grafting.
-Partial Ulnar nerve grafted to Long Triceps.
-Uninjured C7 Hemi-Contralateral cross-over to Deltoid muscle.
-Wrist flexor tendon transfer to middle, ring, & pinky finger extensors.
Surgical medical facility:
Brachial Plexus Clinic at The Mayo Clinic, Rochester MN
(all surgeries successful)
"Do what you can, with what you have, where you are."
~Theodore Roosevelt - Location: Los Angeles, California USA
Re: New Approaches to Spinal Cord Regeneration
Mike W,
Thank you for writing them and posting their response here! It's important for these researchers to know that their work is appreciated and realize that actual human beings are waiting and in need of a cure.
The issues they address in the bottom paragraph; the avulsion reconnection barrier and that chronic older injuries build a scar type barrier are being addressed by other researchers in the field and they are all having good success.
This problem of researchers not knowing what other researchers are doing and not being able to collaborate was one of the main goals of the Christopher & Dana Reeves Paralysis Act that Obama finally passed after years of sitting on the Senate floor and being denied by the Bush administration. Getting researchers to be aware of each others' work and join forces when able, will accelerate efforts towards a cure and eliminate pointless redundant & wasteful research.
I think he Tufts study is extremely encouraging especially considering what else is going on out there.
Chris
Thank you for writing them and posting their response here! It's important for these researchers to know that their work is appreciated and realize that actual human beings are waiting and in need of a cure.
The issues they address in the bottom paragraph; the avulsion reconnection barrier and that chronic older injuries build a scar type barrier are being addressed by other researchers in the field and they are all having good success.
This problem of researchers not knowing what other researchers are doing and not being able to collaborate was one of the main goals of the Christopher & Dana Reeves Paralysis Act that Obama finally passed after years of sitting on the Senate floor and being denied by the Bush administration. Getting researchers to be aware of each others' work and join forces when able, will accelerate efforts towards a cure and eliminate pointless redundant & wasteful research.
I think he Tufts study is extremely encouraging especially considering what else is going on out there.
Chris
Re: New Approaches to Spinal Cord Regeneration
22 years later...I am still rejenerating my nerves...remember there are millions of them ..
I am grateful that throught the guidance and grace of God and some extremely skilled surgeons I had the courage and the patience to be enduring the recovery of my arm. Keeping busy and self healing is equally important along with holistic medicine for spasms, pain, etc..Science is not an absolute and it's pioneers...all of us that spear these researchers forward to find answers, because we demand so...
Making Medical History myself with my own TBPI and being on a lecture schedule with doctors that journeyed from around the World to meet and study me. Although I felt like a specimen at times, I also realised how much I was helping them and other TBPI...All our contributions to all our doctors collectively will continue to break new ground in spinal cord repair.
I am grateful that throught the guidance and grace of God and some extremely skilled surgeons I had the courage and the patience to be enduring the recovery of my arm. Keeping busy and self healing is equally important along with holistic medicine for spasms, pain, etc..Science is not an absolute and it's pioneers...all of us that spear these researchers forward to find answers, because we demand so...
Making Medical History myself with my own TBPI and being on a lecture schedule with doctors that journeyed from around the World to meet and study me. Although I felt like a specimen at times, I also realised how much I was helping them and other TBPI...All our contributions to all our doctors collectively will continue to break new ground in spinal cord repair.