|
Faculty Professor Joan Abbott Director, Centre for Neuroscience Kings College, London, UK The blood-brain barrier: a challenge for CNS drug discovery Neural signalling requires precise homeostatic regulation of the interstitial fluid (ISF) of the brain. The blood-brain barrier (BBB) formed by the brain endothelial cells lining cerebral capillaries not only contributes to this regulation, but also protects the brain from neuroactive and potentially toxic compounds circulating in the plasma. The ‘barrier' is a complex of physical restriction (tight junctions reduce paracellular permeability for hydrophilic molecules), transport regulation (uptake and efflux carriers and selective transcytosis regulate transcellular molecular flux) and metabolic activity (enzymes metabolise many potentially harmful agents). This ‘multitasking' BBB has played a major role in the evolution of the brain as a complex and integrated neural network, but poses problems for therapeutic approaches that require the delivery of drugs and other molecules to the brain for the treatment of CNS disorders. Better understanding of the potential routes across the BBB, and more accurate measurements of BBB permeability to molecules covering broader chemical space, are leading to better prediction of BBB permeation for novel drug candidates. They can also help guide medicinal chemists on ways to optimise entry to the brain for CNS drugs, and to reduce CNS side-effects of drugs designed to act peripherally. Prediction for passively penetrating compounds is now relatively good, but carrier-mediated transport, especially for efflux, is less well understood or characterised, and structure-activity relationship (SAR) approaches have proved less practical than expected. Moreover, new transporters at the BBB are still being discovered. The free drug concentration in brain ISF may not be accurately predicted from measurements of brain: plasma ratio (logBB), and the dynamics (flow, turnover) of ISF also need to be taken into account. A combination of in silico (computer-based) modelling and measurements on model systems (both in vitro and in viv o) can help to guide the screening, design and selection of compounds to target or to avoid the brain. For larger and more polar compounds shown to have useful activity on CNS targets, novel ways to by-pass the blood-brain barrier may offer therapeutic strategies for the future. Changes in BBB permeability and function are recognised in a number of neurological conditions requiring drug therapy, and this adds to the complexity of predicting CNS drug PK: PD in patients. There are opportunities for pharmaceutical and biotechnology companies to work together with basic science research groups to tackle these issues, to facilitate better measurement and prediction of BBB drug penetration and brain distribution. (*Wolfson CARD, specialising in basic and applied Neuroscience) Professor Vincenzo Libri, MD, PhD Trials designed to evaluate clinical outcomes based upon conventional testing are of long duration, highly subjective and variable and, therefore, expensive. Thus, it is critical to develop any laboratory or physical tools, to be used either alone or in combination as an alternative outcome for clinically meaningful endpoints. While markers endpoints may not be the true predictor of a real clinical endpoint, they may provide initial indication on whether the intervention is sufficiently promising to justify the conduct of larger-scale. and longer-term clinical trials. Only reliable biomarkers biomarker can be used to guide decisions to progress compounds to further development. To prove useful, biomarkers should be easily and non invasively (or moderately invasively) detectable in living subjects, as well as results should be reproducible over a short period of time with small test-retest variability. Also, biomarkers should be positively correlated to the progression of the disease and/or the pharmacological target of interest. Overall, markers should either be correlated to the causal pathway of the disease process (disease-based surrogate marker), or recognise the mechanism of action of a potential new therapy, and therefore be of use in determining central penetration and/or optimal dose (mechanism-based marker, or biomarker). Either way, the relation between marker endpoint and intervention should have a biologically plausible explanation. A marker validation process is currently needed as results may not be available in the literature or they ramain to be reproduced over-time and across different labs or species. Accordingly, markers endpoints should be investigated in both animals and humans, as the extrapolation of animal models of disease to human pathology is often uncertain, as well as false positives and/or false negatives may occur. A validation process is also required for a better definition of the marker sensitivity, specificity, positive and negative predictive value, accuracy, likelihood ratio of positive and negative tests, discriminant validity, sensitivity to change and to treatment difference. Only an accurate process of marker/method validation would allow conclusion as to whether marker endpoints may support Go/No Go decisions at early stages of CNS drug development. Dr. Thomas Rosahl, Ph.D. Research Fellow, Dept. of Molecular&Cellular Neuroscience Merck Sharp & Dohme Neuroscience Research Centre, Terlings Park, Eastwick Road, In vivo Strategies to select compounds with clinical efficacy Benzodiazepines remain to be a major first line treatment for most anxiety disorders. However, beside their beneficial anxiolytic and anticonvulsant effects, benzodiazepines have also several undesirable side effects including tolerance and dependence. As a strategy for further drug optimisation, we used knock-in mice carrying BZ binding site alterations to dissect out the various effects of BZ on individual GABA-A receptor subunits. Results on those knock-in mice corroborated the concept of developing subtype selective BZ with similar anxiolytic properties, but less side effects, than currently used BZ. The second part of the talk takes a more general look at recent developments in transgenic and phenotyping technologies, which may allow to increase the predictive power of model organisms for the clinic Dr. Lars Sundstrom Chief Scientific Officer, Capsant Neurotechnologies, Bassett Cresc. New in vitro models of acute brain injury based on cultured brain slices. Applications for target validation and lead optimisation studies. Acute brain injuries such as stroke and traumatic brain injury account for around 10% of the global burden of disease (Olesen and Leonardi 2003). Developing new therapies for acute brain injuries has proved challenging and the vast majority of therapeutic strategies involving small molecules have so far failed. Several reasons have been put forward to explain the lack of ability to translate experimental findings into clinical benefits, including the lack of availability of suitable in-vivo and in-vitro animal models. The use of simple tissue culture systems involving cell lines and or acutely dissociated neurons, which have been used in the past, may have contributed to biasing the selection of lead candidates towards targets that are ineffective in the reality of a clinical setting. For in-vitro models to more accurately reflect pathological mechanisms, they must retain functional aspects of brain tissue (e.g. neuronal connectivity). We have been developing a new generation of in-vitro models based on the organotypic culture of slices of rat brain tissue that retain functional connectivity and fundamental characteristics of brain tissue that are lost in more simple preparations. We have developed new models of acute and chronic brain injuries in these models that accurately reflect disease processes seen in-vivo and we have shown that these models respond much more accurately than simpler in-vitro systems to pharmacological treatments known to work in-vivo. We are now extending the scope of these in-vitro models to discovering new compounds and therapeutic approaches as well as developing new technologies that will allow target validation in complex in-vitro systems. Dr. Paul Whiting, B.Sc (Hons) Ph.D. Senior Director, Molecular and Cellular Neuroscience, Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR CNS disorders and their treatment: progress and prospects Despite many decades of effort, our progress in developing new therapies for neurological disorders has been somewhat disappointing and unsatisfactory. Serendipity has played a major role, followed by the development of many “variations on a theme”, particularly in the area of psychiatry. Where known, mechanism of action has generally followed after demonstration of clinical efficacy. The limited understanding of disease mechanisms and how existing treatments work has impeded discovery of more effective therapies. Indeed, a new drug discovery paradigm based on defined molecular mechanisms and understanding disease will be necessary for the development of completely new therapies. Breakthroughs in the genetics, together with the tools of the post genomics era such as transcript profiling, proteomics and systems biology offer great hope in moving towards this goal. However the task of unravelling the patho-physiology of complex, often progressive, syndromic disorders should not be underestimated. It will be some years before the fruits of these labours emerge. Professor Steve Williams Professor of Imaging Sciences, Institute of Psychiatry, Kings College, The contribution of neuroimaging to CNS drug discovery: progress and prospects Until recently imaging had been used almost exclusively to aid in the diagnosis of individual patients in order to guide therapeutic decisions. However, in the past few years, we have experienced an ever increasing effort to broaden the scope of this technology into medicines research. We are now making a concerted effort to refine many of these medical imaging techniques in order to facilitate the development of marketable pharmaceutical products. Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI), the major cornerstones of brain imaging, are both playing an increasingly important role in drug development. In recent clinical trials, these modalities have been used not only to refine our subject inclusion/exclusion criteria but also to evaluate whether a drug has reached the target organ and whether it has produced the desired biological effect. Currently, one of the major objectives of neuroimaging research (for the pharmaceutical sector) is the development of “biomarkers” which offer the potential for more timely and quantitative data than traditional trial endpoints of morbidity and mortality. We hope that such biomarkers will allow more efficient and accurate pharmaceutical evaluation thus decreasing both the time and costs involved in the drug development process. During my talk I will present a series of recent examples where imaging has helped to expedite “go” or “no go” decisions for several putative therapies in a range of neurological and psychiatric indications. The CNS disorders that I will review include multiple sclerosis, dementia, stroke and schizophrenia. Some examples where imaging has helped to facilitate the translation of pre-clinical disease models to the clinical environment will also be discussed. I will also review the latest developments in “smart” imaging agents as well as recent advances in hardware that may allow us to combine the strengths of these multi-faceted techniques. |
|
|
Webcast produced by Prous Science © Prous Science 2004. RealNetworks, RealPlayer and RealAudio are trademarks of RealNetworks, Inc. |