Background of Central Nervous System (CNS) Drug Discovery
Over the years, the discovery of drugs for treating CNS diseases has proven to be one of the highest risk areas in the pharmaceutical industry. Although huge resources have been invested, it remains a fact that a significant number of approvals have been for new formulations, incremental improvements to existing therapies, or the use of known drugs in different clinical settings. The challenges facing CNS drug discovery are multifactorial and are apparent across the process of drug discovery and development process. Despite enormous investment in basic science and preclinical research, this has not led to improved success in demonstrating efficacy in Phase II and III trials.
Strategies for CNS Target Identification and Validation
Target identification (determining the correct drug targets for a disease) and validation (demonstrating an effect of target perturbation on disease biomarkers and disease end-points) is a process to accumulate the evidence for and against a target, and drug developers typically spend 12-18 months conducting new research or replicating literature studies to build sufficient evidence. In recognition of past failures that used conventional strategies to identify and validate targets, novel strategies that may increase the probability of success of delivering new CNS therapeutics are currently being employed by many drug development organizations.
Ideas for new targets come from a variety of sources, including in-house target identification campaigns, in-licensing opportunities, and, perhaps most importantly, the public domain in the form of published findings and public presentation of data at conferences. Resources are then designated for validation.
Back translation (reverse translation), also called bedside-to-benchtop research, begins with actual, real-life patient experiences in the clinic, or during a clinical trial, and works backward to the pre-clinical drug discovery space, to uncover the mechanistic basis for these experiences and clinical observations. In this translation paradigm, research becomes a seamless, continuous, cyclical process, in which each new patient observation stimulates new testable hypotheses that help refine and direct the next iteration of benchtop therapeutics research, which, in turn, leads to the next clinical trial and the next human experience. Back translation can particularly inform discovery and early clinical development via appropriate quantitative integration of relevant data. Accordingly, this strategy may enhance the identification and validation of the novel target.
Base on the understanding of disease pathophysiology, much progress has been made to identify novel targets for the treatment of neurodegenerative disorders. Alzheime’s disease (AD) represents an interesting example. A pathology-based approach has been used to discover potentially disease-modifying treatments for AD. The combination of genetics and molecular pathology has contributed to an understanding of the role of amyloid production in the pathogenesis of AD, and several potential drug targets have been identified in this pathway.
Recent advances in understanding the architecture of the genetic risk in neuropsychiatric disorders have opened up the possibility of identifying novel targets based on an understanding of disease pathophysiology. The identification of disease-associated genetic variation is the initial step in determining the involvement of genetic risk. The next step is the translation to the molecular mechanism. Once mechanisms are identified, signaling pathways and the process of target identification can begin. Model systems, such as genetically modified animals in which risk gene(s) may be knockout or knockin, are an essential component for identifying and validating novel targets.
Despite great progress in our understanding of the process and different strategies for CNS drug identification and validation, the discovery of new drugs and their clinical development for many CNS disorders has still been problematic. With industry-leading expertise and state-of-the-art single-use equipment, Creative Biolabs is committed to providing high-quality service of CNS drug discovery, focusing on innovative research and development. Our team has extensive experience in psychotropic drug development, providing accurate and effective solutions for researchers all over the world. Please contact us for more information and a detailed quote.
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