During the past quarter century, there has been the tacit assumption that knowing the specific genetic etiologic mutations for inherited diseases would lead immediately to great flashes of insight regarding treatments. More recently, similar assumptions have been made for susceptibility variants for more common diseases. The fundamental process for finding medicines usually requires the identification of tractable targets to screen molecular libraries for hints and leads, whether high-throughput or traditional techniques are used. The problem facing the pharmaceutical industry and neurotherapeutics is that there are only a relatively few classes of tractable targets (7-transmembrane repeats, nuclear receptors, kinases, etc), and the identified genetic variants or proposed etiologic processes do not lend themselves to screening.
The Human Genome Project, as well as the development of inexpensive computers and bioinformatics, has provided the tools for high-throughput screening to determine differences in tissue metabolism. Nowhere is this more critical than in neuropsychiatric diseases, where in the past the pathological leads have at times been vague and where "chemical imbalances" are known to play an important role. Comparative gene expression applications have been available for several years, with high cost and variable success. The development of sophisticated high-throughput proteomic analyses will be the next technologic development to impact this area. The goal is to determine where a therapeutic effect on human disease could be focused, targeted, developed, and registered.
APOE was the first susceptibility polymorphism system to be confirmed as a susceptibility gene for a major disease, Alzheimer disease. However, APOE is not a tractable target. This talk will review gene-to-function-to-target studies using modern genomic and proteomic technologies to identify metabolic pathways and potentially new tractable targets for drug discovery and development.
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