Discovering Targets for New Therapies: The Role of Basic Science

BY STEVEN E. HYMAN, M.D.

In contrast to many other fields of medicine that address themselves to chronic or recurrent diseases, psychiatry is fortunate to have a substantial number of efficacious drugs. Despite the laudable efficacy of our now diverse armamentarium of antidepressant, antipsychotic, and mood-stabilizer drugs, we recognize that we are not yet in a position to cure or prevent mental disorders.

To address this deficiency, the National Institute of Mental Health has invested heavily in genetics and fundamental neuroscience research. In this column, I would like to address some of the ways in which these basic disciplines can impact the development of therapies.

Central to modern processes of drug development is the concept of a drug target; that is, a molecular target against which compounds can be tested for inhibitory or facilitatory activity as is appropriate. In psychiatry, the development of effective drug treatments began with a series of serendipities. Beginning with the identification of lithium by John F. Cade in 1949, these continued with the identification of chlorpromazine, the first antipsychotic drug, and then imipramine and the MAO inhibitors, the first antidepressant compounds.

As was the rule during the 1950s, the actual molecular targets of antipsychotic drugs and antidepressant drugs only became known after the drugs were known to be efficacious. The precise molecular target of lithium remains a matter of debate, although there are at least two highly compelling candidates. Based on the efficacy of existing antipsychotic drugs, the D2 dopamine receptor family and much later, based on properties of clozapine, the serotonin 2a (5-HT2a) receptor were identified as molecular targets for antipsychotic drug development. In the case of antidepressant drugs, the monoamine reuptake transporters, most notably the norepinephrine and serotonin reuptake transporters, were identified as drug targets, and more recently a host of other synaptic proteins within noradrenergic, serotonergic, and dopaminergic synapses have been identified as potential targets for the development of antidepressant drugs.

As a result of the exploitation of these molecular targets by the pharmaceutical industry, we now have antipsychotic drugs that may have enhanced efficacy and both antipsychotic and antidepressant drugs that have fewer side effects than older compounds. As good as our existing treatments are, however, what we need are fundamentally new treatments directed at the actual pathophysiology of mental disorders—treatments that may one day prevent disease onset or progression or that may cure. To move beyond drug targets derived from the action of existing treatments to targets related to pathophysiologic processes requires the tools of neuroscience and genetics.

There is a very important example of just such a development unfolding at the present time that may lead to new treatments for Alzheimer’s disease. Success is not yet certain, but there are very promising leads that illustrate the power of neuroscience and genetics to identify drug targets involved in the fundamental disease process—which could lead, in this case, to treatments that would slow or halt progression.

A great deal of research from biochemistry, genetics, and neurobiology has pointed to the likelihood that a small fragment of the beta-amyloid precursor protein (a specific form of the so-called A-beta fragment) is pathogenic in Alzheimer’s disease. Much important biochemistry led to the identification of this fragment, but the major breakthroughs arguably came from genetics. While the common varieties of Alzheimer’s disease appear to be genetically complex—that is, resulting from multiple genes (including the ApoE locus) and nongenetic factors—a small percentage of familial Alzheimer’s disease of early onset results from Mendelian transmission; that is, the dominant inheritance of a single locus is sufficient to produce illness. Genetic linkage studies in early-onset families identified multiple mutations in three different genes, the beta-amyloid precursor itself and genes encoding the previously unknown proteins presenilin 1 (PS-1) and presenilin 2 (PS-2).

To summarize a long and interesting story, it appears that the beta-amyloid precursor protein can be cleaved in three positions to produce different fragments that are then released into the extracellular space, where under normal circumstances they may be involved in cellular growth and maintenance. However, the A-beta fragment has a tendency to precipitate out and form pathogenic amyloid deposits. Each cleavage site involves a different protease; since the fragments are ultimately secreted, these protein-cleaving enzymes are referred to as the alpha, beta, and gamma secretases. If the beta-amyloid precursor is cleaved by the alpha secretase, the resulting fragment is not pathogenic. It is the action of the beta and gamma secretases that together release the A-beta fragment that may lead to amyloid deposition. The little-understood gamma secretase recently has been thought perhaps to be presenilin 1 or else closely associated with it. The mutations that produce early-onset familial Alzheimer’s disease bias these processes toward the production of pathogenic A-beta fragments. It now appears likely that other genetic variants that have been implicated in late-onset Alzheimer’s disease, such as ApoE4 and certain alpha2-macroglobulin alleles, may impact the metabolism of beta-amyloid and its cleavage products as well. This information has led to a massive race among pharmaceutical companies to produce inhibitors of the beta and gamma secretases.

Although this beta-amyloid story is not yet proven with certainty, these two secretase molecules have become important drug targets, the inhibition of which would interrupt the pathogenesis of Alzheimer’s disease. Should the story prove to be correct, and should safe and effective inhibitors be found, we would have truly incredible new weapons to alter the course or even prevent Alzheimer’s disease.

NIMH has been one source of support for the genetics of Alzheimer’s disease, and we are proud of our contributions. We invest on a considerably larger scale in research on the genetics of schizophrenia, autism, manic-depressive illness, and early-onset depression. These are disorders in which, in aggregate, genes have a pronounced role in pathogenesis. If there are families in which these disorders are caused by single genes, we have yet to isolate them. More likely, the genetics of these disorders will be much more complex than those that characterize the early-onset Alzheimer families and that led to the breakthroughs outlined above. Nonetheless, by finding vulnerability genes we hope to be pointed toward actual pathogenic pathways into which we can intervene directly. Also, by determining when in brain development these genes are active, we will be better able to time our interventions.

The scientific challenges promise to be long and hard. They will require not only genetics research, but, as we investigate the actions of genes, they also will require the work of many neuroscientists and behavioral scientists, often, perhaps, addressing questions that may appear to be far removed from the treatment of mental disorders. But through such efforts, coupled with translational studies and sophisticated clinical insights, valid drug targets related to pathogenesis will be discovered and will have an immense impact on the treatment of mental illness.