Despite well over four decades of research, we have yet to develop a therapeutic for the spinal cord injured patient that produces a robust clinical improvement. In the research setting, efficacy of a candidate therapeutic is often defined in highly reproducible rodent models of spinal cord injury (SCI). However, the challenge with this approach is that a beneficial effect is rarely studied in the context of different injury severities and it is even more rare for efficacy to be further validated in a second species. Without these additional steps, there is risk that beneficial findings of a therapeutic, solely tested in a rodent model of SCI, will not translate to a similar beneficial outcome in the spinal cord injured patient.

We propose a unique two-species approach to investigate the drug GM6001. This drug blocks the activity of proteolytic enzymes, known as matrix metalloproteinases (MMPs). Early studies in a mouse model of SCI have suggested that blockade of MMPs will improve clinical outcomes. We and others have shown that MMPs are increased in the mouse spinal cord within the first days after SCI and this increase is associated with greater tissue damage. We have found that GM6001 when given 3 hours after a moderate level of SCI in mice enhances their neurologic recovery. That is, animals treated with a vehicle show very limited hind limb function whereas those treated with GM6001 are able to take coordinated weight-bearing steps. Here we will test the benefits of this drug in mice that have been subjected to a more severe SCI and will determine if this drug is efficacious when treatment is initiated beyond the first 3 hours after injury. Together, these studies will tell us about the potential limitations of GM6001 in terms of window of therapeutic opportunity and effectiveness in more severe SCIs. Our primary focus for these studies is on neurologic and urologic function. We will determine if spinal cord injured mice that show hind limb paralysis will be able to assume greater locomotor function when treated with GM6001 as compared to vehicle controls. As SCI results in loss of voluntary control over bladder function, we will also determine if GM6001 reduces bladder dysfunction.

In a complementary series of experiments, we will study the efficacy of GM6001 in spinal cord injured dogs. Spontaneous SCIs occur in certain dwarf breeds of dogs and result from the spontaneous rupture of disks that are an integral part of the backbone. Rupture of a disk damages the underlying spinal cord and results in varying degrees of hind limb paralysis. Disk herniation is a common cause of paralysis in the pet dog population, is a natural injury as is the case in humans, and in many respects mimics what happens in people with SCI. Preliminary data show that MMPs are elevated in these dogs, thus supporting our hypothesis that these enzymes may cause further damage to the spinal cord similar to what we have found in the injured rodent spinal cord. In the proposed studies, the information from our rodent studies will be used to design a pet dog preclinical trial that will examine both neurologic and bladder outcomes in animals that receive either drug or vehicle. Preliminary data show that GM6001 is safe to use in dogs at doses shown to be efficacious in the rodent. Our veterinary colleagues at Texas A&M University see approximately 125 dogs annually that present with spontaneous SCIs. Thus, we are in an ideal position to conduct a preclinical trial in this population. Validation of efficacy in both the murine model of SCI and in dogs with spontaneous SCIs will serve as a solid platform for translating this effort to human clinical trials. GM6001 provides the first test of efficacy of a general MMP inhibitor to treat SCI. With success of these studies and optimization of this drug or a related MMP inhibitor to make it compatible for intravenous delivery, we expect that clinical trials could be underway in approximately 5 years.