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Thread: Stephen Davies Lab Report

  1. #1
    Senior Member Schmeky's Avatar
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    Stephen Davies Lab Report

    Laboratory Visit

    On July 10th and 11th, 2006, I visited the lab facility of Stephen Davies on invitation, located in the Baylor College of Medicine, Houston, Texas. I was afforded a tour of the lab facility and was shown a laser-scanning (confocal) microscope for 3D imaging of tissues with sophisticated image reconstruction software, tissue culture facilities, and a lab rat being surgically yet humanly altered for lab testing. The facility was clean and modern with a total staff of 6 researchers. There was very little conversation within the lab, everyone was concentrating and working on specific projects. I was impressed by the conscientious work nature everyone exhibited during my visit. Stephen Davies exhibited urgency and enthusiasm about his work.


    The Role of Decorin in SCI

    In 2004 Jeanette E. Davies et al., studied the role of Decorin, a small leucine-rich proteoglycan. In previous studies Decorin has been shown to reduce astrogliosis (the reaction of support cells called astrocytes to injury) and basal lamina formation in acute spinal cord injuries (SCI). Davies tested the effectiveness of Decorin utilizing a mini-pump infusion method into acute stab injuries of the adult rat spinal cord. Investigation revealed that Decorin not only limited the formation of astroglial limitans, but also reduced the deposition of axon growth inhibitory proteoglycans neurocan, NG2, phosphacan, and brevican more than 80%. Decorin induced changes in scar formation combined to promote the striking ability of axons from microtransplanted adult sensory axons to enter, grow within, and exit Decorin infused spinal cords. The ability of Decorin to promote axon growth across acute spinal cord injuries through a coordinated suppression of inflammation, chondroitin sulfate proteoglycans (CSPG) expression and astroglial scar formation make Decorin treatment a promising component of future SCI regeneration strategies.

    In 2006 Jeanette E. Davies et al., investigated the role of spinal cord scar tissue as a combined physical and molecular barrier to axon regeneration. As the 2004 study indicated, Decorin effected a major suppression of acute inflammation, astrogliosos, and multiple axon growth inhibitory CSPG, thus promoting rapid axon growth across the injury site. The high efficiency of CSPG core protein suppression suggests that Decorin may promote CSPG degradation (breakdown) in addition to suppressing CSPG synthesis. Plasmin is an enzyme that can degrade axon growth inhibitory CSPGs and other molecules such as collagen that are found in acute and chronic scar tissue. It is first made in pro-form called plasminogen that has to be cut to make active plasmin. Plasminogen can be made by microglia. The objective of this study was to see if Decorin infusion into the adult rat spinal cord could increase plasminogen/plasmin synthesis. Results indicated infusion of Decorin over the first 8 days post SCI resulted in 10- and 17-fold increases in plasminogen and plasmin protein levels, and a 3 fold increase in microglial plasminogen mRNA in tissue culture. In addition to potentially degrading multiple axon growth inhibitory components of the glial scar, plasmin is known to play major roles in activating neurotrophins and promoting the ability of the central nervous system to make new connections.

    These 2 research papers clearly show the effectiveness of Decorin in injured spinal cords to significantly reduce scar formation and promote robust axon growth across the acute injury site. Therefore Decorin appears to be both neuro-protective in it’s ability to suppress inflammation and simultaneously neuro-regenerative. Consequently, Decorin has the potential to be a very significant factor in functional recovery in acute SCI.

    Since Decorin is effective in the acute phase of SCI, there is early evidence that it may also be effective in the chronic phase as well. Testing of Decorin in the chronic phase of SCI is presently taking place in chronic rats and results should be available by the end of 2006.


    The Limited Success of Embryonic Stem Cells in SCI

    Transplantation of embryonic stem cells (ESC) has been a strategy used in the repair of the central nervous system (CNS). Success has been limited since the ESC’s were cultured into neural progenitor cells and it was anticipated the transplant environment would provide the necessary signals to achieve a degree of regeneration in SCI. Transplantation of these cells alone to acute SCI has not resulted in robust axon regeneration beyond the injury sites, which could be due to the progenitors differentiating into cell types that support axon growth poorly and/or their inability to modify the inhibitory environment of the adult CNS.

    These results suggest that neural progenitors need to be differentiated (turned) into a cell type that has the capability to promote a higher degree of axon regeneration capable of expressing growth beyond the injury site.


    Astrocytes Derived from Glial-Restricted Precursors

    In 2006 Jeanette Davies, et al. investigated the role of differentiating astrocytes from embryonic glial-restricted precursors (GRP) in acute SCI recovery. Transplanted GRP derived astrocytes (GDA) promoted robust axon growth and restoration of locomotor function after acute transection injuries of the adult rat spinal cord. Results indicated growth of over 60% of ascending dorsal column axons into the centers of the lesions, with 66% of these axons extending beyond the injury sites. GDA transplantation also induced a striking realignment of injured tissue, suppressed initial scarring, and rescued axotomized CNS neurons with cut axons from atrophy.

    Conclusion: Pre-differentiation of glial-restricted precursors into a specific type of GDA before transplantation into SCI leads to significantly improved outcomes over precursor cell transplantation, providing a novel strategy and a highly effective new cell type for repairing CNS injuries. Rats treated with these cells recovered near normal walking ability as measured on a walking grid. 26 out of 26 rats using this strategy showed the same degree of recovery.

    This means the stage is now set for emerging therapies that have proven to be very effective in the lab setting. It would appear as though the missing factor is overcoming the chronic injury scar/lesion.


    Combination Strategies

    Strictly on a personal note, I would think the environment is ripe for a combination of Decorin combined with astrocytes derived from GRPs, at least in the acute stage of injury. I would speculate that recovery based on this combination could be “spectacular”, exceeding the significant recovery observed using either one of these single successful modalities alone. This is strictly a personal observation on my part. It would only seem logical to attempt this combination sometime in the near future. This may be the road map to truly effective functional recovery, a result the SCI community could conceivably refer to as a “cure”.


    Chronic Injuries

    One of the more difficult aspects to overcome in chronic SCI is a scar tissue at the site of injury , a structure that rapidly forms in the first 24 hours post injury (i.e. molecules such as CSPGs are deposited first) and develops further as a combined molecular and physical barrier, following the days, weeks, and months after injury.

    In the 2006 research paper referenced under the heading “The Role of Decorin in SCI”, Decorin induced the injured spinal cord to make the serine protease “plasmin” which can degrade axon growth inhibitory CSPGs and other scar associated molecules. Administration of Decorin in the acute setting resulted in 10- and 17-fold increases in plasminogen and plasmin protein levels, and a 3 fold increase in microglial plasminogen mRNA in vitro. In addition to potentially degrading multiple axon growth inhibitory components of the glial scar, plasmin is known to play major roles in activating neurotrophins and promoting central nervous system plasticity.

    The question is, can Decorin produce similar results in the chronic scar/lesion? Even if the effects of Decorin in the chronic scar were less than what has been observed in the acute lesion, it could potentially produce a more receptive environment for other cellular based therapies to prove beneficial enough for functional recovery.

    Decorin expresses plasmin, which has been shown to have the capacity to activate neurotrophins and promote CNS plasticity. The good news is Davies lab is testing Decorin in the chronic setting today. Preliminary results should be available by the end of 2006, perhaps sooner.


    Collaboration

    Davies lab is collaborating with other labs/pharmaceuticals in areas of replication and the manufacture of Decorin. Additionally, other research groups working with Davies lab are identifying specific axon tracts that enervate the bladder and produce penile erection. This research can potentially produce targeted areas of regeneration that have the ability to generate a greater overall effectiveness of functional recovery.


    Previous Therapies

    Davies discussed the applicability of his labs emerging therapies to individuals that have elected to have past SCI treatments offered by Lima, Kao, Huang, Cells4health, and at Novosibirsk, Russia, to name a few. Davies research with astrocytes from glial precursors is based on cell types that are naturally occurring in the spinal cord, not cells that are foreign to the spinal cord. However, of course this does not mean that you will not be granted access to new treatments in the future, it just means that you may have to wait for a treatment to be fully FDA approved, effectively excluding one from future clinical trials. Consequently, it would be difficult and costly to test each treatment to ascertain effectiveness. There are potential problems where the effectiveness of future therapies may be compromised or in the worst case, prove to be ineffective when combined with a previous therapy. In summation, patients that have not received previous therapies would most likely take precedence over those that have elected to have prior restorative therapies.


    Comparison to Other Research Organizations

    At the recent Working to Walk rally held in Washington, D.C., a few prominent and well-known research organization spokespersons indicated there are presently no “blockbuster” treatments in their research pipelines that could produce functional recovery in the chronic contused spinal cord. We can only hope this is not the case since any and all progress made towards recovery is positive.

    Additionally, most of the work of other well-known labs is based on remyelination of denuded axons. In cases of severe damage to the spinal cord, what if an insufficient number of axons are not present that could benefit from remyelination? It would appear the best approach would be to remyelinate and regenerate. However, what if regeneration efficiencies of 10% or higher could be consistently achieved? This would mean more people would benefit, even those with insufficient numbers of denuded axons remaining.

    Therefore, based on this observation, it would seem prudent to pursue therapies that produce the most consistent and robust regeneration of new axons.


    Clinical Trials

    I asked Davies how his emerging therapies could get into clinical trials as soon as possible. One option I inquired about was the ChinaSCINET currently being organized by Dr. Wise Young. Davies indicated he would utilize this network if it were made available in the future. He indicated to me his objective is to get his lab results translated to humans as soon as safely possible.

    The North American Clinical Trial Network is an additional option although at this point it is in need of substantial funding.

    The Christopher Reeves Paralysis Act is an additional source of getting promising therapies into clinical trial. This bill has been stalled for over 3 years but passage with dedicated funding could create a US based infrastructure capable of initially carrying out clinical trials.

    When can one reasonably expect to get promising therapies into clinical trial? It would be hoped in 5 years or less, however the timeline is not yet defined. Funding is the key element, which is currently unavailable in the USA. Setting up a clinical trial infrastructure is time consuming and costly.

    However, if a documented, replicated lab therapy is positively identified, it would hard to imagine Congress NOT funding such a trial. Based on Davies research article: Astrocytes derived from glial-restricted precursors promote spinal cord repair, Journal of Biology, March 22, 2006, it would appear there is presently compelling evidence to argue for funding. With a modest investment by the Government, substantial long-term savings could be realized.


    Funding

    Davies indicated his funding is secure only until August, 2007. It is becoming increasingly more difficult for SCI labs to sustain funding. Bio-terrorism and AIDS research funding have higher priorities than SCI research. This is unfortunate since breakthroughs seem to be close at hand. Davies hopes the strength and significance of his lab results will allow his funding to continue, however, politics can sometimes impede progress. As mentioned earlier, there are only a small handful of labs working on reversing chronic SCI. Davies lab is one of these, which fortunately appears to be making progress.


    Conclusion

    There are many labs worldwide searching for effective therapies to reverse the effects of SCI. As mentioned previously, there are only a few labs doing chronic research. Based on my personal observations and after reading the research papers authored and co-authored by Davies, his lab appears to be very close to producing significant results. Certainly there are other labs working diligently to achieve the same objective and I encourage CC Forum members to seek out these labs and gain as much information as possible and share their findings on this forum. I am not aware of any lab that has produced the degree of regeneration in the acutely injured spinal cord as Davies lab. Perhaps someone with more scientific knowledge than I may interpret Davies papers differently.

    I am not a representative nor am I a spokesperson for Davies lab, nor am I endorsing or making any recommendations. I am merely an observer and a report writer. I have done my best to accurately convey my findings at Davies lab devoid of bias or prejudice.

    Any technical questions should be addressed to Stephen Davies: sdavies@bcm.edu

  2. #2
    Senior Member spidergirl's Avatar
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    The 5 year deal? i feel like this is a movie we all speak of.

    Nevertheless, thank-you David. One can never say that you don't contribute greatly to the community.

    Overcoming this glial scar perhaps is the most difficult thing in chronic SCI and if in fact Davies replicates this...he is a true hero of our time.

    *only time w/ tell

  3. #3
    Quote Originally Posted by spidergirl
    The 5 year deal? i feel like this is a movie we all speak of.

    Nevertheless, thank-you David. One can never say that you don't contribute greatly to the community.

    Overcoming this glial scar perhaps is the most difficult thing in chronic SCI and if in fact Davies replicates this...he is a true hero of our time.

    *only time w/ tell
    Thank you, David. I think we all agree in need for a solid clinical trial infrastructure and increased funding for this type of research.

    ~dan
    Daniel

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    Senior Member Quadcessible's Avatar
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    Thank you for the well written informative article. From what you posted it seems this Dr. has a good understanding and approach to possibly moving the cure along. I realize many people here don't have a positive outlook toward the Miami Project, but it occured to me that they do seem to be a leading network of independent funding and have staff capable of assisting reasearch and replication of the studies done to date, it may be worth looking into. Just a thought.

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    Senior Member Schmeky's Avatar
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    I hope the report is not to "wordy". I have tried to be concise and cover all the bases.

    It should be evident that we are "extremely" close to a real breakthrough. Significant functional axon regeneration has already been achieved, a major milestone.

    If Decorin is effective in the chronic contused scar, we could be in business.

    I hope to visit Davies lab at the end of 2006, first of 2007, when his chronic research should be evident.

  6. #6
    Great post. Thanks.

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    Senior Member NWC4's Avatar
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    Much thanks Schmecky! Need to reread it and let it soak in. I eagerly await your future visit with the Davies and another encouraging report.

    Did the good doctor indicate any strategy (other than the possible use of the SCIChinaNet) or a time range for moving to human clinical trials if the Decorin results in the chonic rats are as positive as he suspects? Speaking of wordy. Or was he more mindful of first things first, go where the data/results take you.

    Thank you Doctors Davies!!

  8. #8
    schmeky, excellent summary! I learned from reading it. Wise.

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    Senior Member lynnifer's Avatar
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    Thank you both .. excellent report Schmek ... should the Masters in Electrical Engineering not get you anywhere (yeah right!) .. you could always write for medical journals!

    I feel a bit angry that AIDS gets more research money than SCI. Some people won't like that statement - but they've had their heyday (what 20yrs of research now?) and the condition is now stable with medication allowing a normal span of life. I'm not saying it should stop .. but it can be prevented. SCI cannot.

  10. #10
    David,

    Thank you for your succinct summary and taking the time to write it. Your optomism is evident--that means a lot as you, over time, have become a barometer check in terms of realistic therapies on the horizon.

    Susan

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