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Translational Neuroscience Research Lab

Focus on Cognitive and Psychiatric Disorders

Central nervous system (CNS) disorders, such as Alzheimer’s disease and schizophrenia, are some of the most prevalent and devastating human illnesses wit few effective treatment options. Despite enormous drug discovery and development efforts in the Neurosciences, few novel therapies have entered into the marketplace in recent years in part due to a high rate of attrition plaguing these efforts. In general, the average success rate for a new drug to receive regulatory approval for treatment of human diseases across therapy areas is very low, around 11%; however, it is much higher for some areas (e.g., cardiovascular diseases ~20%), and lower for others including CNS (~8%).

Lack of efficacy in clinical development is cited as one of the largest reasons for the high attrition rates with ~30% of drug failures due to this cause. Alarmingly, the attrition rate due to lack of efficacy has remained largely unchanged from 1991-2000, whereas other variables contributing to poor success rates in clinical development have shown dramatic improvements during this same time period (i.e., pharmacokinetics) (Kola & Landis; Nature Reviews Drug Discov. Vol 3; 2004). These data highlight the importance of improving the translation of preclinical findings more effectively into the clinic for CNS disorders.

One important approach to reducing attrition rates in clinical development is to improve the validity of the preclinical models used to support advancing drug candidates. Measuring CNS function (e.g., learning and memory, mood) is inherently complicated in a preclinical setting; however, choosing appropriate systems that model the targeted disease state or that represent more accurately the cognitive and mental capabilities of humans (e.g., higher order species) may help.

SRI has a highly validated and customized Translational Neuroscience Research (TNR) laboratory that employs non-human primates (NHPs) operantly trained on basic lever pressing machinery and/or on the Cambridge Neuropsychological Automated Test Battery (CANTAB™). The purpose of the lab is to facilitate early clinical development by designing preclinical studies that will directly translate into a human population. In addition, pharmacokinetic-pharmacodynamic relationships can be established in the behaving NHPs that allow for better efficacy and safety estimates that have been used to inform clinical study design. Some key features of the TNR lab include:

•  Forward and backward translation
• Uniquely positioned at the interface between drug discovery and early clinical development
• Uses include profiling novel drug candidates, as well as informing clinical study design
• Pharmacologically validated and sensitive assays that can assess both improvements and impairments in behavioral function
• Extensive pharmacological model validation
• NHP behavior is individually titrated based on performance criteria to optimize model sensitivity
• Test assessments currently include, but are not limited to:
• Working Memory (Delayed Match-to-Sample; Paired Associates Learning)
• Attention (Object Retrieval)
• Impulsivity (Differential Reinforcement of Low-Rate Behavior)
• Antidepressant Efficacy (Differential Reinforcement of Low-Rate Behavior)
• Side Effects (Catalepsy,Locomotion, Sedation, Extrapyramidal Symptoms)
• Pharmacokinetic (Plasma, Serum,Cerebrospinal Fluid)
• Biochemical (e.g., Prolactin)

Employing NHPs as an intermediate step between rodent and human efficacy determinations provides a unique opportunity to improve drug discovery efforts, reduce costs and enhance our fundamental understanding of learning and memory in NHP and human brain function.

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       Last Updated Feb 1, 2012