Background and Rationale of the Forum
According to the World Health Organization,1 brain and nervous system disorders are the leading cause of disability worldwide and the leading overall cause of disease burden in established market economies. With changing global demographics, specifically an increasing proportion of the world’s population living past 60 years of age, the relative burden of brain disorders is projected to increase markedly within the next 2–3 decades. The potent influence of these disorders on disability stems from the fact that the brain is the organ of thought, emotion, and behavioral control. To varying degrees, brain disorders result from the interaction of genetic risks factors and developmental and environmental factors, ranging from early malnutrition to severe stress (exacerbated globally by prolonged, serious conflict in many regions). The effects of these disorders on individuals, families, and society are enormous. Early onset disorders, such as autism, epilepsy, schizophrenia, and mood and anxiety disorders, disrupt personal development and are potent causes of disability. Neurodegenerative diseases impact an increasingly large segment of the world’s population and, like early onset disorders, affect not only the sufferer, but also their families (e.g., caregivers must often devote their entire time to care). Finally, disorders such as depression are well documented to exert a malign effect on the course of other chronic diseases, such as heart disease and diabetes.
Despite the impact of diseases of the nervous system on individuals and society as a whole, our current arsenal of therapies to treat CNS diseases effectively is extremely limited and dated. The efficacy of major classes of drugs to treat depression, anxiety, schizophrenia, and bipolar disorder reached a plateau nearly a half century ago, and despite promising research, disease-modifying treatments for neurodegenerative disorders have not yet materialized. In spite of the dire need, the complexities of such diseases and the challenges of successfully developing new therapies have prompted many large pharmaceutical companies to abandon further efforts. Among their reasons were: (a) the heterogeneity of many brain disorders and the need in many cases to rely on descriptive diagnoses, (b) the lack of knowledge of the fundamental causes and mechanisms of most diseases, (c) a lack of animal models that translate to human and predict treatment efficacy, and (d) a lack of objective human biological markers with which to conduct clinical trials.
Concurrent with the exit of industry, however, neuroscientists, geneticists, chemists, bioengineers, and clinical investigators including psychiatrists, neurologists, and neurosurgeons are finally at the threshold of discovering pathobiological mechanisms and identifying molecular, cellular, and neural circuits that can be addressed using specific and targeted therapies. Over the past decade, several breakthrough technologies have emerged, and new approaches continue to arise that allow unprecedented insights into brain function and, consequently, would enable the discovery and development of new drugs, as well as therapeutic devices. For example:
- Imaging: Unlike peripheral diseases, we typically do not have the ability to sample brain tissue. Therefore, a variety of high-resolution imaging modalities have become vital tools.
- Biomarkers: Development of disease-specific biomarkers is being used to test drug engagement with the target and/or to serve as surrogate markers of efficacy in human studies.
- Personalized Healthcare: Relevant criteria for patient stratification are needed in this area, similar to other successful examples seen in other difficult therapy areas (e.g., in oncology).
- Circuit Analysis: New, minimally invasive techniques have emerged over the past five years that enable the delineation of normal and abnormal neural circuitry. Optical control of neural circuits has allowed us to map synaptic networks involved in specific symptoms in live animals.
- Genomics and Genetics: The human genome project has prompted the development of powerful new technologies. With modern genomic tools, the first replicable results have appeared for schizophrenia, autism, bipolar disorder, and common late onset forms of Alzheimer’s disease.
- Gene Silencing and Regulation: shRNA, RNAi, and microRNA technologies offer large-scale screening opportunities for functional characterization of genes that may become drug targets.
- Stem Cell Technologies willpermit, for the first time, a supply of human neurons that can be studied to understand disease pathways and screened for new agents.
- Drug Screening Technologies: Cell-free and cell-based micro- and nano-screening technologies that probe targets of neural significance, such as GPCRs, ion channels, synaptic and even intraneuronal targets, have been developed and are being applied with success.
- Blood-Brain Barrier Penetration Technologies: Several high-capacity transporter molecules have been identified that can carry therapeutically active molecules across the blood-brain barrier.
- Neurostimulation Devices: Implanted, transcranial, and other electrical and magnetic technologies have been developed that offer increasingly precise control of specific nerves.
- Simulation-based research: Brain simulation has the potential to provide new insights into the basic causes of neuropsychiatric diseases and new ways to test therapies and understand the way they work by providing a test platform that can directly target the causes of disease.
To address the global burden of CNS disease, collaboration is essential. Oncology has set a most impressive example of how discoveries have been translated into a wide range of effective treatments, including small molecules, antibodies, and biological agents, over a timeframe of 20–25 years, starting with the discovery of oncogenes, kinase receptors, angiogenesis, patient stratification and personalization based on genetics and genomics. Solid science has led to effective therapies. A similar transformation is needed for CNS diseases and can be anticipated based on recent scientific breakthroughs. What is exceedingly important at this stage is to envision and define a roadmap that will guide future discovery and development efforts. The time is ripe to bring together the leading minds in the field to define a roadmap for future discovery and development efforts in this vitally important area.
1 The Global Burden of Disease: 2004 Update. WHO 2008: ISBN 978 92 4 156371 0
Top of page