Richard J. Zeman, Ph. D.; New York Medical College; PRMRP Investigator-initiated Research Award

We're developing a novel treatment for spinal cord injury. And, most treatments are given by injection systemically and so they affect the whole body and then find their way to the injured spinal cord. However, the problem is that the injury blocks circulation so the agent that's injected can't get to the injury site. So, we chose X-irradiation and this can penetrate the tissue without a need for viable circulation so the therapeutic agent completely penetrates the injury. The relevance for the military is that of the spinal cord injury cases in the United States, a quarter of those are veterans. So, they're overrepresented so the CDMRP is a major funder of this kind of research. Other treatments for spinal cord injury have to find a way through the circulation to the target but nobody knows what the target is. So, we began these studies to dissect out in the injured spinal cord where the therapeutic target is. We use a rat model of spinal cord injury. We drop a weight onto the spinal cord and this produces an injury that's reproducible and then the next step is to produce a radio surgery program in which multiple beams will be aimed at the spinal cord to focus radiation on the spinal cord. We follow the rats after treatment with a system for determining how well they are able to move or to walk or to locomote. And, we have a scale for rating the animals and then we plot over a period of 6 weeks the scores, and in control rats that receive no radiation, the scores plateau at a lower level than in rats that received this treatment. This proves that irradiating the spinal cord itself is beneficial for recovery. So, then, we wanted to pinpoint the target for the treatment so we subdivided the spinal cord into different segments with the injury site right in the middle. We found something interesting. As we progressed from the tail to the head, we get more and more recovery. So, the best recovery is seen at this region here. So, this is somewhat surprising because we would suspect that the injury site itself would be the therapeutic target. But, it turned out that it wasn't. Then, at the same time, we looked at the animals, we sectioned them, we look at their spinal cords, and we can measure how much tissue is left at each level of the spinal cord in treated animals and untreated animals. And, again, the irradiating at this position here which is closer to the head compared to the injury site we saw the best recovery. We did an analysis in which we correlated the recovery locomotor function with the sparing of tissue at each of these levels and found an almost perfect correlation closer to the head compared to the injury site. So, this, we believe, is the optimal therapeutic target. We have some ideas about what is here that might be so important for recovery. So, recently, some experiments were done in which in recovering rats who had spinal cord injury, if a small population of neurons, called propriospinal neuron was ablated or killed off at this point the recovery was completely lost. So, they seem to be critical for recovery and it appears that we're actually treating this population of cells. And, that implies that the actual target is much smaller so we like to refine our techniques so we can examine that hypothesis that these are the true targets. Our next step will be to further optimize the target and then if we can prove that it works, then it can be used in clinical trials with human patients.