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Translational Research

 

Annamaria Vezzani

In the last decade, basic science has contributed significantly to the knowledge of the molecular mechanisms underlying the generation of seizures and their recurrence. Preclinical studies have provided a better characterization of the homeostatic and maladaptive mechanisms occurring during the process of epileptogenesis. The use of in vivo and in vitro experimental models reproducing part of the salient neuropathological and EEG features of genetically determined or acquired epilepsies, and the availability of more sophisticated molecular and imaging techniques have been instrumental to achieve these tasks.

Deeper insights into the mechanistic hypothesis of epileptogenesis and occurrence of spontaneous seizure have inspired novel approaches of therapeutic intervention. These could provide more efficient seizure control with less side effects, particularly for those types of epilepsy difficult to treat with conventional antiepileptic drugs. Additionally, intervention on the mechanisms envisaged to play a crucial role in disease progression could provide novel means to develop curative, and not merely symptomatic, treatments. Once again the use of in vivo experimental models of genetically determined or acquired epilepsies is a key point to obtain the proof-of-principle of applicability of a novel treatment to a clinical setting. In this frame, emphasis should be put on translational research, namely the translation of basic discoveries into clinical applications including scientific validation of experimental results, the development and validation of new therapies and prognostic or diagnostic surrogate markers of disease.

As a matter of fact, it proved difficult to translate effective therapeutic approaches in the animal model into human trials. Part of the problem is certainly the huge investment for the sponsors of clinical trials and the scientific community that the step from animal model to man means. Moreover, establishment of standard methods on how to perform preclinical development of novel putative neuroprotective/antiepileptic treatment in epilepsy models is lacking. Recommendations for standards regarding preclinical drug development have been provided in published documents for stroke (Stroke.1999; 30:2752-2758) and ALS/MND (ALS; 2007, ePub ahead of print) with the intention to provide guidelines for “rigorous, robust, and detailed preclinical evaluation to have a reasonable chance to succeed in an appropriately designed clinical trial.” 

On the basis of these considerations, the Commission On Neurobiology, together with the Commission on Therapeutic Strategies, feels that it is essential to revisit the current methods of antiepileptic drug screening, with the goal of enhancing the existing screens in a way that will predict ultimate clinical efficacy/effectiveness more consistently. Leading members of these two Commissions and the Secretary-General of ILAE, nominated members of “The ILAE Neurobiology/ Therapeutic Strategies Joint Commission” to conduct a research project with the aim of obtaining insights into the validity of models used in the identification of anticonvulsant/neuroprotective activity. This goal stems from the belief that more accurate prediction of clinical success will encourage the selection of truly promising compounds for clinical development.

The first step would be to convene a work group of academic epilepsy researchers, representatives from the pharmaceutical industry, and individuals associated with regulatory authorities. This group would discuss available data of drugs that came to clinical trial, successful and unsuccessful, with the goal of determining what in the existing panel of preclinical screens and data were most predictive of clinical success. It will be important to include a number of potential data points such as neurological side effects, toxicity and pharmacology, not just screens for efficacy.  To assure that the outcome of this endeavor has broad consensus support, it is essential that the effort involve the broader community of those interested in developing improved epilepsy therapies, including academia, government and industry. The next step will be to examine the published information that has been validated through clinical experience. Once this information had been reviewed, the project team would obtain proprietary data on as many failed compounds as possible from industry sources. The third step would be to examine the profile of each drug in preclinical testing and determine if there are models that are consistently positive in preclinical testing and fail to show efficacy in clinical trials. These preclinical models would be considered “not validated.” Other preclinical models might have been negative for the failed drugs, but an examination of marketed drug would show that they were predictive of efficacy. These preclinical models would be considered “possibly validated.” A similar type of analysis could then be performed for various seizure types and syndromes, if adequate experimental and clinical data were available. A first meeting to discuss this strategy has been scheduled during the AES Annual Meeting in Philadelphia.

A second major approach of the Commission on Neurobiology to translational research is to foster a bidirectional communication and exchange of information between basic scientists and clinicians. This task will be achieved by organizing workshops, joint sessions and educational activitites in the frame of the main national and international epilepsy meetings. Recent examples of these activities include the 1st Latin-American Summer School on Epilepsy, São Paulo (Brazil) organized together with the Educational Committee (E. Cavalheiro), the WONOEP 2007, and the joint scientific sessions organized with the Commission on Genetics at the Singapore 27th IEC Congress. These initiatives are focused on topics that can bridge experimental work with the clinically relevant questions related to etiopathological mechanisms and innovative therapeutic approaches.

Annamaria Vezzani
Commission on Neurobiology Chair


 

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