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Epilepsy Benchmark IC1

Research @ NINDS
Epilepsy
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Judith Hoyer Lecture on Epilepsy

Curing the Epilepsies 2013: Pathways Forward

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Contacts
Brandy Fureman, Ph.D.
Program Director, Channels Synapses & Circuits Cluster
furemanb@mail.nih.gov

Deborah Hirtz, M.D.
Program Director, Division of Extramural Research
dh83f@nih.gov

John Kehne, Ph.D.
Program Director, Anticonvulsant Screening Program
john.kehne@nih.gov

Randall Stewart, Ph.D.
Program Director, Extramural Research Program
rs416y@nih.gov

Vicky Whittemore, Ph.D.
Program Director, Channels, Synapses & Neural Circuits Cluster
vicky.whittemore@nih.gov

 

Epilepsy Benchmark IC1

Benchmark Area I: Understanding basic mechanisms of epileptogenesis

Section C: Validate and apply models of epileptogenesis and epilepsy as biological test systems for novel therapy

Specific Benchmark 2: Design a strategy for validating animal models of epileptogenesis, and determine the efficacy of a limited number of proposed antiepileptic treatments in validated models of epileptogenesis.  The strategic approach will include arriving at a consensus on the current models of epileptogenesis, and identifying a scientific approach for validating the potential utility of future models for the study of human epilepsy.


2005 Report submitted by Benchmark Steward(s):
H. Steve White, Ph.D. (University of Utah)
James Stables, M.S.A. (National Institute of Neurological Disorders and Stroke)

Background of the benchmark goal:  As with all classes of drugs, the discovery and development of new AEDs rely heavily on the employment of preclinical models to demonstrate efficacy and safety prior to their introduction into human volunteers.  Obviously, the more predictive an animal model(s) for a particular seizure type or syndrome, the greater the likelihood that the investigational AED will demonstrate efficacy in human clinical trials.  Herein lies one of the most often discussed issues in the current-day AED discovery process; i.e., what is the most appropriate in vivo/ in vitro model system(s) to employ when attempting to find comparable efficacy in human epilepsy patients? 

Current status of field:  Since 1993, nine new AEDs have been introduced for the management of partial epilepsy. Currently there are also several new compounds in various stages of clinical development. These discoveries and their subsequent development have predominately been based on activity either the maximal electroshock, s.c. Metrazol, or kindled rat models of generalized and partial seizures.  Their introduction into the treatment armamentarium has clearly had an impact on the lives of patients with epilepsy through improved seizure control, a lessening of adverse events, improved pharmacokinetics, and fewer drug-drug interactions.  Unfortunately, despite the availability of these new therapeutic options, a significant fraction of the patients with epilepsy continue to live with uncontrolled seizures, often at the expense of significant drug-induced adverse events.  Clearly, there is a need for more efficacious therapies that will not infringe on a patient’s quality of life.  The successful identification of more effective drugs will depend on the identification and validation of models that more closely resemble human epilepsy.             

Activities update: 

  • Planning for a Models Task Force Meeting to review progress/barriers in models for antiepileptogenesis (AEG) along with unique pharmacology in the pediatric and elderly systems.
  • Awarded 6 grants in the area of AEG and pharmacoresistance (PR). Also, people are now reporting numerous research activities in the area of AEG & PR.

Top priorities for next 5-10 years:

  • Develop a community-wide data base of pharmacological results forthcoming from RFA supported grants
  • Define a mechanism for selecting and testing investigational therapy in newly defined epilepsy model (Task Force topic)
  • Determine the feasibility for incorporation of newly identified and validated model systems of AEG & PR into NINDS sponsored screening program testing the most novel candidates to these new systems.
  • Continue to shepherd efforts to support model development for catastrophic pediatric epilepsies and geriatric epilepsy that can be incorporated into therapy screening programs. 
  • Develop a consortium of investigators that have an expressed interest in characterizing novel therapeutics in a more diverse battery of the highly labor intensive, low throughput animal models
  • Develop collaboration with other Benchmark Stewards in an effort to incorporate novel findings into ongoing therapy discovery programs             

Roadblocks to progress:

  • Low through-put associated with most chronic epilepsy animal models
  • Recognition that translational support will promote progress in both basic and clinical outcomes.
  • Lack of validated miniaturized video-telemetry recording units that can be employed in genetic mouse models.  Need to develop and apply new technology in these areas.
  • Paucity of laboratories interested in conducting therapy screening and trained whole animal pharmacologists with expressed interest in translational research.

References:

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Last updated January 12, 2010