Columbia SMA Project: MMP-9 as a Potential Therapeutic Target

Background: Spinal muscular atrophy (SMA) is a genetic disease of childhood which leads to muscle weakness and, in severe cases, death of the patient. Because disease results from mutations in the SMN1 gene, most therapeutic strategies focus on restoring SMN protein to normal levels. Although there have been several exciting developments over the last years, no compound or treatment has yet been successful in the clinic. Therefore, it is still urgent to investigate other means of delaying onset or slowing progression of the disease. One way to do this would be to identify the factors that act downstream of SMN depletion to cause motor neuron degeneration, and to identify means of inhibiting them.

Objective/Hypothesis: The general hypothesis underlying this study is that by better understanding the molecular mechanisms through which eye movement and continence are preserved even in late-stage SMA patients, we may directly identify targets for therapeutic intervention in this currently incurable disease. The specific hypothesis tested is that resistance of oculomotor and Onuf's nucleus motor neurons is linked to their selective lack of expression of matrix metalloproteinase-9 (MMP-9), and therefore that inhibition of MMP-9 in vulnerable motor neurons should delay the onset and/or progression of disease.

Study Design: To test this hypothesis, and hopefully to validate MMP-9 as a therapeutic target, we will first assess disease-resistance of motor pools in mouse models of SMA and the extent to which this correlates with MMP-9 expression (Technical objective 1). Subsequently, we will perform genetic studies of the role of MMP-9 in motor neuron susceptibility in SMA model mice (Technical objective 2). Lastly, we will test candidate MMP-9 inhibitors in pharmacologic studies of the role of MMP-9 in motor neuron susceptibility in SMA model mice (Technical objective 3).

Relevance: The objective is to identify disease-modifying agents in animal models of this currently incurable disease. This would in itself have direct relevance for families suffering with SMA. In addition, discoveries of treatments effective in spinal muscular atrophy are relevant to health outcomes in the military for several other reasons. First, much evidence also links MMP-9 to amyotrophic lateral sclerosis (ALS), a devastating adult-onset disease which occurs with increased frequency in Gulf War veterans. Second, further insights into mechanisms of neuronal cell death are relevant to a wide-range of conditions, such as traumatic brain injury, which are frequently encountered in the military during action in the field.