Editorial: Challenges and Opportunities in Neuroscience Research (2012)

The need for new and effective treatments for neurological and psychiatric diseases has never been greater. As a larger percentage of the population reaches advanced age, the prevalence of neurodegenerative diseases including Alzheimer's disease and Parkinson's disease has increased. For example, more than 36 million people currently suffer from Alzheimer's disease—by 2050, this number is expected to grow to more than 100 million people worldwide with a predicted annual cost of $1.9 trillion. In many instances, psychiatric diseases such as schizophrenia, bipolar disorder, and depression strike young adults, and often these disorders are associated with a lifelong burden. Given the need for new pharmacological approaches to these devastating diseases, it is surprising that the level of investment in discovering new treatments has been in decline. In the face of strong economic pressures, many large pharmaceutical companies have re-evaluated their research portfolios and reduced their investment in neuroscience drug discovery. Investment in small biopharmaceutical companies focusing on neuroscience drug discovery has similarly waned as the overall return on investment is now perceived in many cases to be less favorable compared to other diseases. For example, developing new pharmacological approaches for neurodegenerative diseases that offer the promise of disease modification as opposed to symptomatic treatment can be costly with significant risks for development and an overall success rate that is comparatively low. Developing novel treatments for disorders of the central nervous system (CNS) is indeed a complicated and uncertain venture. In the past several years, few CNS medicines have been successfully registered as drugs, and many of these newly approved drugs work via established mechanisms of action with limited differentiation from existing therapies. The successful development of CNS drugs with novel mechanisms of action such that they are differentiated from the current standard of care is rare. The human brain is a highly evolved organ and many CNS disorders, especially those that are believed to have a developmental component, are not observed or easily modeled in animals. In many cases, the pathophysiology of human CNS diseases is uncertain, and symptoms from one disorder can often be present in another disease. The heterogeneous nature of most human CNS diseases complicates the elucidation of underlying pathophysiology and can frustrate those seeking to evaluate investigational drugs in the clinic. Typically, placebo response rates are high, resulting in a higher rate of failed trials. Furthermore, if validated human disease biomarkers are absent, and they frequently are, then the clinical evaluation of a novel CNS agent might not inform any further about the promise of the mechanism of action but rather signal a dead-end for the molecule and program. Developing new models with broad predictive validity for neurodegenerative and neurodevelopmental disorders has been elusive. Most pharmacological animal models have been validated for agents acting through established pathways and usually do not have wide applicability outside of a certain mechanistic domain. For example, the available animal models for depression and schizophrenia could be helpful in picking the next selective serotonin reuptake inhibitor or atypical antipsychotic but might not identify an agent for these illnesses that works via a novel mechanism of action. Developing predictive models of human neuroscience diseases that provide translation to the clinic is a critical need. Without advancement in these models, progressing CNS drugs that work through novel mechanisms of action into the clinic will continue to carry the same risks. A second critical need is to develop translatable biomarkers from the preclinical domain through clinical evaluation. For many CNS disorders, developing noninvasive biomarkers is vital, and progress is being made in several areas. Electroencephalography (EEG) methods can directly record minute changes in the brain's electrical activity over short time intervals. These recordings can be analyzed to reveal distinct changes across the spectra of frequencies present in the brain. Changes in the EEG can be responsive to stimuli including the administration of centrally active drugs. Magnetoencephalography (MEG) is another noninvasive technique being developed to monitor brain function with extremely high temporal resolution. Functional magnetic resonance imaging (fMRI) allows researchers to track neuronal activity across various regions of the brain. Positron emission tomography (PET) allows researchers to quantitatively assess receptor occupancy through displacement of a radiotracer with an investigational drug molecule. Medicinal chemists can play an important role in developing PET tracers by designing ligands with appropriate levels of receptor affinity, selectivity, brain penetration, and desirable physicochemical properties to maximize signal-to-noise sensitivity. PET molecules developed in this manner can have utility in assessing target engagement in preclinical animal models as well as providing measures of receptor occupancy in the clinic. With these types of vertically translatable tools available, the evaluation of novel CNS mechanisms and the corresponding predictive validity of related animal models can be a much more informed undertaking, allowing a more definitive assessment of a new mechanism of action. In the face of these daunting challenges, what are the prospects for medicinal chemists working in the field of neuroscience? Medicinal chemistry remains an essential component of neuroscience drug discovery, which is a highly interdisciplinary endeavor whereby neuroscientists and chemists are highly dependent on one another for advancing understanding in this field. As prospective CNS mechanisms are evaluated preclinically, it is critical to have small-molecule probes that have good selectivity and activity against the target. Chemists need to develop tool compounds that freely penetrate the blood–brain barrier without high levels of nonspecific binding. The brain remains a privileged compartment in the body and identifying molecules that have the correct physicochemical characteristics, as well as resistance to CNS efflux transporters, is important. Unlike other peripheral tissues, the use of antibodies or other modalities for target validation in the brain is less tractable, so small molecules remain critical to this mission. Medicinal chemists have developed greater facility in designing molecules that readily diffuse into the brain and can quantify concentrations of these molecules in the brain through the use of preclinical imaging, cerebrospinal fluid sampling, and microdialysis. The development of well-behaved probe molecules goes hand-in-hand with advancing understanding of new CNS targets. Understanding of the relationship of neurological and psychiatric diseases with certain human genetic mutations continues to expand understanding of neuropathophysiology. For example, certain genetic mutations now associated with Parkinson's disease, bipolar disorder, and schizophrenia have provided new insights into disease targets and mechanisms. With careful science and disciplined decision making, these pathways can be evaluated and insight into the mechanisms of human disease can be obtained. For example, studies on mutations of the canine gene Hcrtr2 (encoding orexin receptor 2) have revealed the central role of the orexin pathway in regulating wakefulness and provided opportunities for novel therapies for sleep disorders. Other human genetic associations have been important for generating new hypotheses for Alzheimer's disease pathology (PSEN1 and ApoE4) and Parkinson's disease (SNCA, LRRK2, PARK2). Studies are revealing significant genetic heterogeneity among CNS diseases that contribute to a spectrum of clinical symptoms. This could provide new prospects for targeted, personalized approaches and avoid some of the pitfalls associated with clinical trials of large populations with related but etiologically diverse symptoms. While treating underlying disease pathology remains an important goal, developing new treatments for certain symptomatic clusters can potentially find application across a range of CNS disorders and address critical unmet medical needs. For example developing drugs that enhance cognitive function could have utility in multiple disorders where cognitive impairment is present including schizophrenia, Alzheimer's disease, and Parkinson's disease. Increased awareness of the gap that currently exists between understanding the origins of diseases of the brain and developing novel therapies has provoked increased interest in collaboration across consortia of private foundations, government and academic laboratories, and the pharmaceutical industry. Academic and industrial laboratories are beginning to develop models for sharing knowledge and specialized capabilities to bring the strengths of both groups to bear on the challenges of CNS diseases. Nonprofit foundations are also contributing larger sums to fund translational science, thereby providing additional means for academic groups to develop novel ideas beyond basic science. Small translational drug discovery centers are emerging at many large medical centers, and these groups help provide links between basic researchers and the realities of drug development. The challenge for medicinal chemists working on CNS disorders has never been greater. The low-hanging fruit might have been picked, yet these initial discoveries—many made decades ago—leave a lot of room for improvement. However, advances in understanding the intricate workings of the brain and how these neuropathologies take hold, in combination with developments in target engagement and biomarkers of disease, now offer new avenues to pursue. Working with this new knowledge and their colleagues in biology, medicinal chemists can address what are some of the most devastating and costly illnesses society faces. Given the impact of these diseases, it is imperative there be a continued investment in CNS drug discovery. We cannot afford otherwise. 1 Dr. Paul J. Coleman Merck Research Laboratories West Point (USA) 1 Prof. James C. Barrow Lieber Institute for Brain Development Johns Hopkins School of Medicine Baltimore (USA)