A Comparison Between Researchers and Spinal Cord Injured Individuals

Opinions on the Preclinical Evaluation of Novel Therapies for Spinal Cord Injury Kwon BK, Ghag A, Reichl L, Dvorak MF, Illes J, Tetzlaff W.

Source: University of British Columbia, Dept. of Orthopaedics, Vancouver, British Columbia, Canada; brian.kwon@vch.ca.

Abstract

We previously conducted a survey to garner the opinions and perspectives of scientific and clinical researchers on what levels of preclinical evidence were needed in order to justify translating a promising neuroprotective or neuro-regenerative therapy in spinal cord injury (SCI) into a human clinical trial (Kwon et al., 2010). Here, we conducted an analogous survey of individuals living with spinal cord injury in which we garnered their expectations for the levels of preclinical evidence achieved by researchers in substantiating the neuroprotective and neuro-regenerative therapies being offered to them in clinical trials. In total, 214 individuals with SCI completed the survey, and their responses were compared to the responses of the 235 scientists and clinicians who completed our previous survey. SCI individuals were more likely than SCI researchers to opine that demonstrating efficacy and safety in rodent models of SCI alone is sufficient to proceed with clinical trials. However, SCI individuals also reported strong support for large animal and primate model studies, and in the case of the latter, were actually more in agreement for the need for primate studies than researchers. SCI individuals also reported a strong support for independent replication studies. In general, individuals with SCI had high expectations for the levels of preclinical evidence required to justify translating novel therapies into clinical trials. These expectations should be considered in the decisions to translate specific experimental therapies for spinal cord injury.

The comments posted below from some of the 235 researchers and clinicians are as interesting as the article itself in addition to the perspective of people with SCI.

J Neurotrauma. 2012 Jul 9. [Epub ahead of print]
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5 Responses to A Comparison Between Researchers and Spinal Cord Injured Individuals

  1. Anonymous says:

    In response to several questions and comments at the Care Cure Forum about the Kwon et al article and about what constitutes a chronic injury, I have decided to add my comments here at the U2FP website where the Kwon article was first posted. I am excited to become a regular contributor ( and I will encourage my neuroscientist colleagues to join me) to this new and exciting venue where we can discuss issues related to spinal cord injury at the very highest level of scholarship and decorum. Depending on the type of injury to the spinal cord, a wide array of destructive phenomena occur over time that can effect the efficacy of any purported therapy. Contusive injury when very strong is among the most severe types of cord lesions because the resulting damage covers a relatively wide, football-shaped area compared to a more narrow surgical lesion. Relatively soon after injury, the initial physical trauma itself following by bleeding and ischemia almost immediately kills a certain portion of the tissue within the cord depending on the severity of the initial event. Gray matter is severely compromised but white matter also succumbs. However, this initial loss of neurons and their axons as well as glial elements is followed by a period of secondary untoward phenomena largely related to the consequences of having free blood in the CNS and the very nasty actions of the immune system which can lead to a far greater loss of cells and their processes. So- called pethechial hemorrhaging occurs for many hours to over several days and allows for even further bleeding into the cord. This series of events continually erodes tissue so that far greater damage is done to the cord than that created by the initial injury itself and the lesion expands greatly. Because of the complexities of the many biological phenomena involved with this relatively early secondary injury period, a vast array of treatments have been reported to impact, in a positive way, these early destructive phases of the secondary injury cascade. Stem cells of a variety of types can clearly ameliorate some of these damaging events. It is difficult to pinpoint for certain how long this second degenerative phase of destruction goes on but I would suggest that it occurs for a period of time far greater than just 2 weeks (here I differ, as it appears I often do, from Dr. Young over at CareCure).

  2. Anonymous says:

    We know that dying back of axons can go on for well over a month in a dorsal column crush model and it has been documented that oligodendrocytes continue to die at sites well away from the initial lesion for many weeks. Most SCI researchers I know would never agree that 2 weeks post injury could be considered “chronic” and it is still possible that neuroprotective strategies could save tissue well beyond 2 weeks. Most people agree that about 6 weeks after injury in any species puts you into the beginnings of the chronic phase. Many would classify this time period between 2 and 6 weeks as sub-chronic and approaching several months after injury most would consider chronic. Also, and importantly, once the death phase is largely over after the first several weeks or so there still are various other untoward events that can occur gradually for years after injury. Axotomized neurons atrophy over extended periods of time and change their basic physiology. As the cell bodies atrophy their shrinking dendrites may loose synapses from their connecting neurons. New and perhaps mal-wired connections slowly form and reconnecting them without other manipulations could result in worsening rather than improved behavior. Also, over extended periods of time (months to years) and due to the loss of axons, astrocytes in the white and gray matter distal to the lesion become incredibly dense and along with increases in the perineuronal net matrix these slowly developing events form strong barriers to axon growth and plasticity. We also now know that over time the chronically dystrophic tip of the severed axon that persists indefinitely in the lesion penumbra makes synaptic-like connections with resident stem cells, so these tips are truly stuck in the scar. It will surely be necessary to take steps to free them or awaken them as time passes. Thus, there are numerous events that occur over time (some occurring quickly some occurring very gradually) following SCI that can all dramatically affect the outcome of any proposed strategy aimed at fostering repair. That is why I have and will continue to defend the position that it is imperative to perform critical pre-clinical experiments on animals before moving into humans showing not only safety but also efficacy using appropriate lesion models but also with an appropriate lag time following injury.

  3. Anonymous says:

    I suggest this is especially true if we are to treat humans at a full year after injury. In my opinion one simply cannot and should not argue that because some treatment or combination of treatments is minimally effective at 2 weeks or less after contusive injury in a rodent that we should jump right into humans. Long chronic experiments in animals, while admittedly costly and difficult, can and should be done and I believe we should first show far more than just safety before we move into humans. After all, if what we are proposing to do on people turns out not work at all in an appropriate animal model of chronic injury then, even if we do little harm, wouldn’t it be better to continue the basic research in order to discover something else that does work well in truly chronically SCI animals? I cannot condone "experimenting" on humans and I believe that we need more than a "strong therapeutic rationale for showing that a therapy is effective." I think we need to show actual efficacy. The question of whether one needs to show both safety and efficacy in a large animal whose size and immune system is more like ours is also a matter for debate and some would argue that the pig model might be most affordable and akin to human. Can we move from rodent to human if the results in chronic rodent models are promising? I think here the answer could be, yes, especially if the pre-clinical results are truly robust. Thus, I generally agree with the results of the Kwon et al paper and, indeed, I was one of the 235 scientists and clinicians who participated in the first survey. I must say that it was an especially interesting and enlightening experience.

  4. Anonymous says:

    "I am excited to become a regular contributor ( and I will encourage my neuroscientist colleagues to join me) to this new and exciting venue where we can discuss issues related to spinal cord injury at the very highest level of scholarship and decorum"Thank You

  5. Anonymous says:

    Very interesting. I think the survey also shows that in the main people with sci want the research done properly before clinical trials are performed as opposed to having a go on incomplete or inconclusive evidence. In this regard the best researchers and people with sci are on the same wavelength.

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