Recent studies of the first Gulf War veterans with amyotrophic lateral sclerosis (ALS) (often called Lou Gehrig's disease) seem to suggest a direct link of the first Gulf War to this fatal neurodegenerative disease. To date, the cause of the war-related ALS is unclear, although several factors, including environmental toxins, have been hypothesized. However, the hallmark of the ALS pathogenesis remains the same, that is, there is a selective loss of motor neurons in spinal cord and brainstem. It is widely known that these neurons are especially vulnerable to a high level of glutamate. In the cerebrospinal fluid of ALS patients, the glutamate level is abnormally elevated. Indeed, the cerebrospinal fluid from ALS patients is toxic to motor neurons in culture. Glutamate is a neurotransmitter and can activate a family of proteins called glutamate receptors. Glutamate receptors are membrane proteins, and, when bound to glutamate, can form ion channel pores across the membrane that may be highly permeable to calcium. Glutamate receptors may become excessively active when the concentration of glutamate is elevated, as in the cerebrospinal fluid of ALS patients. Consequently, the calcium overload via glutamate receptors may become toxic to cells. Therefore, using inhibitors to dampen the excessive activity of the glutamate receptors may be an effective way to prevent the motor neuron death. In fact, thus far, the only clinical drug that shows a significant benefit to the survival of ALS patients is riluzole, which helps to control the glutamate level.

We want to make a new type of drug that can precisely control the excessive activity of the glutamate receptors. To achieve this goal, we will use a large pool of RNA molecules, which have millions and millions of different shapes or structures; some may have perfect fit to the inhibitory sites on the receptors. We can 'fish them out' by eluting these specific RNA molecules and then find out the molecular composition (cloning and sequencing). These RNA inhibitors (or aptamers) bind tighter, and are naturally soluble in water, which are desirable properties for drugs. Next, we will use a special laser technology to study how these aptamers work, such as which glutamate receptors they prefer to bind (selectivity), and how tight they bind (affinity). An aptamer that has high affinity and selectivity will be more powerful and less likely affect the function of other proteins. The laser technology is needed because the glutamate receptors open the channel within the sub-millisecond time domain. Therefore, the use of laser technology provides a novel and critical method for screening aptamers against functional receptors, which has not been previously possible. We believe that a combination of a better design of inhibitors and better assessment will yield these novel aptamers. These aptamers are valuable drug candidates with special structures that we can mimic to make drugs that are even more powerful. Furthermore, these tight-binding aptamers can be also used as diagnostic probes in ALS detection. We estimate that in about 4 years we will be able to have these unique aptamers. We will then modify these compounds so that they become potent drugs. These aptamer drugs may complement riluzole in that the activity of the glutamate receptors can now be precisely controlled as well. The new drugs may be used as part of a combinatorial/cocktail therapy and may therefore provide added protection and treatment for the war veterans who suffer ALS.