Use of human brain tissue in drug discovery

Despite the success in using animal models to develop drugs which have similar pharmacological properties to those drugs in clinical use, they are much less successful in detecting novel compounds that have pharmacological properties, and possible therapeutic indications, that differ from the drugs that are currently available. In an attempt to improve the chance of discovering novel drugs and, at the same time, reduce the cost and increase the number of compounds which may be screened for their potential therapeutic activity, in vitro models have recently been introduced in pharmaceutical and biotechnological companies based on sequences from the human genome. Such an approach has been encouraged by the need to introduce models based on human brain tissue at a much earlier stage in drug development. In support of this view, it has been estimated that man and chimpanzees share more than 98.9% of their genes in common. However, the expression of genes in the brain was more than fivefold greater in man than in the chimpanzee, whereas the differences in gene expression in the liver and blood were small. Differences between the gene expression of man and rodents were much greater than between man and primates. This suggests that whereas it is possible to model drug metabolism and distribution in such primates, it is less likely that disorders of higher mental function (such as depression and schizophrenia) could be modelled with the same degree of certainty.

Drug discovery in recent years has moved away from the development of specific drugs (such as the SSRIs, 5-HT1A partial agonists, D4 receptor antagonists) which were presumed to act at single targets, to the realization that complex psychiatric disorders require multiple targets for their effective treatment. This change in emphasis in drug discovery is due to an increased knowledge of the interactions that take place between physiological processes in order to maintain homeostasis and the fact that diseases arise as a consequence of a loss of homeostasis. In addition, it is now recognized that many physiological systems have an inbuilt redundancy, whereby the effects of a drug on one system can be compensated by an adaptive change in a closely related system.

In an attempt to model such interactions, cDNA microassays have been developed. Microassay technologies are particularly suited for use with human tissues, including brain tissue, because the widest availability of genes on microchip assemblies has been obtained thanks to the human genome project. Rat and mouse microassays are now also becoming commercially available.

Drug targets are usually proteins. To date, the high-throughput proteomic technologies are not as advanced as the microassay technologies in terms of their sensitivity and number of items which can be determined simultaneously. However, while neither proteomics nor gene expression analysis by microassays are ideal, they are powerful methods particularly when used in combination with in situ hybridization, antibody localization and PCR methods (see Chapter 5 for a discussion of these methods). With regard to the use of human tissues for drug development, stem cells offer a unique advantage over blood cells which have been used as targets for drug discovery in the recent past. Stem cells have a unique property of being able to develop into any cell type, including brain cells. Stem cells have already been used for cell therapy and transplantation therapy (for example, in Parkinson's disease) and more recently they have been used for target identification in drug discovery programmes. As a complementary approach, an analysis of the changes in gene expression using microassay assemblies that occur following the action of known drugs that have been administered acutely or chronically could lead to the development of new classes of drugs with improved therapeutic profiles. A further discussion of the application of these in vitro methods for the discovery of novel psychotropic drugs is given in the reference section at the end of the book.

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