Research and Drug Development for Huntington's Disease
Target Identification and Validation
Basic research on the genes, proteins, and molecular pathways involved in a disease, may assist in the discovery of a biological target. Since there are many genes and proteins involved in most disease pathways, there needs to be a way to identify which ones would be worth targeting for creating a drug therapy. A biological target is a molecule that may hold the key to a disease- it may greatly contribute to, or possibly be the direct cause of a disease.
Validation of the molecule as a biological target usually requires answering two questions. The first asks if the target is relevant to the disease, by examining if a change in the biological target results in a change in the disease. If a certain molecule is produced in a mutated form, in abnormally high quantities, or abnormally low quantities in a disease, it is usually a good biological target. Secondly, if a biological target is proven relevant to a disease, it is then important to determine whether it is drugable - that is, can it be targeted or changed by treatment with a drug.
It is important to remember that validation occurs throughout many stages of the R&D pipeline, including the basic science research, the drug discovery, and the development processes. What may appear effective in a tissue culture model may not work in a mouse model. In each stage of testing or clinical trials, if evidence indicates that a biological target is either not relevant or not drugable, then development of the treatment will stop. The scientists and pharmaceutical companies must then go back to the drawing board. This occurs fairly often, making drug discovery and development a difficult, costly, and time-consuming process. It does not mean that scientists made a mistake earlier on in the process, simply that a different experiment revealed that the target would not be suitable for drug development after all.
HD and Target Identification
A number of biological targets have been identified in the HD research field. First, there is the possibility that the altered HD protein itself may be a good target. It has been well-established as crucial to the disease, but it remains to be seen if it is drugable. Many animal models have shown that once neurodegeneration has begun, elimination of the altered HD protein halts the course of the disease (see Yamamoto 2000 in Cell, or click here for more information). At the same time, little is known about the normal function of the HD protein. We do know that huntingtin is critical for the creation and development of nerve cells, and that mice without the HD gene do not survive to birth (see Reiner 2003 in Molecular Neurobiology, or click here for the abstract.
In addition to the altered HD gene, many other genes, proteins, and molecular pathways have been identified as being involved in the HD disease pathway and its clinical symptoms. We know that molecules involved in energy production, apoptosis, and free radical damage (among others) contribute to HD. It is entirely possible that one of these pathways may have a good biological target that is drugable. For more information about many of the pathways and biological targets being currently examined and developed, click here.
Identifying and validating biological targets is a huge priority in the HD research community. Many basic research labs at universities and private institutions are devoted to this undertaking. The High Q foundation is a non-profit organization that works to bring together academia, industry, governmental agencies, and other funding organizations to identify and validate new therapeutic targets for HD. Recently, proteins like caspase-6 and Poly(ADP-ribose) polymerase (PARP1), have been identified as promising therapeutic targets.
Last Modified: 05/22/2009
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