|John Kehne, Ph.D.
|Meetings and Conferences|
The NINDS Anticonvulsant Screening Program (ASP) screens compounds for anti-seizure activity in a battery of well-established rodent seizure models and was designed to encourage and facilitate the discovery of new therapeutic agents for epilepsy. Researchers from academia and industry in the U.S. and abroad submit compounds to the ASP, and screening is performed at a contract facility based at the University of Utah on a blinded and confidential basis and at no cost to the ASP participant. The NINDS ASP staff reports test results to participants and provides advice on future development steps for promising compounds, while protecting confidentiality and intellectual property.
Since its establishment in 1975, the program has made important contributions to the development of several FDA-approved drugs for epilepsy, including felbamate (Felbatol), topirimate (Topamax), lacosamide (Vimpat), and retigabine (Potiga). Historically, ASP focused on identifying symptomatic treatments for seizure disorders. Following recommendations from a working group of the National Advisory Neurological Disorders and Stroke (NANDS) Council in 2012, current directions for the program place added emphasis on refractory epilepsy, epileptogenesis and disease progression, and epilepsy comorbidities.
A web-based research tool called PANAChE (Public Access to Neuroactive & Anticonvulsant Chemical Evaluations) provides open access to nonproprietary chemical structures and biological data for compounds previously screened in the ASP, including antiepileptic drugs (AEDs) as well as drugs used for other indications. This database is being populated dynamically, beginning with known drugs in the public domain. Compounds submitted to the ASP for testing are included only with permission from the supplier.
Evaluation of submitted compounds begins with a structural comparison within an internal program database of approximately 30,000 compounds. The structural diversity of compounds represented in this database and the wealth of associated biological data provide a wide range of parameters for determining structure-activity relationships that can inform the screening process. Under the direction of the NINDS ASP office, compound screening is performed in a series of validated in vivo/in vitro models. Unless a specific mechanism is known for a submitted compound, qualitative anticonvulsant profiles are determined using two to three different animal models. If deemed biologically active or chemically unique, a compound proceeds into a series of screens designed to establish quantitative, mechanistic, and differentiation profiles for both activity and toxicity. Each stage of evaluation occurs with direct consultation with the participant(s) and ASP staff. The ASP provides feedback on results and an assessment of the potential success of each particular compound or compound class.
See List of Tests for a description of models and tests currently employed in the ASP. In addition, a Program Review Article (PDF, 64kB) provides a general overview of some of these tests and the basic approach applied in screening. The ASP also conducts pilot studies and special projects to develop new models or assess novel mechanisms of action, including efforts relevant to epileptogenesis, disease progression, comorbidities, or specific etiologies.
A signed confidentiality agreement between the NINDS and each potential participant is required before submission of compounds for evaluation. Those interested in participating should contact an ASP staff member for more information and to discuss research goals, resources, and timelines. For compounds approved for testing in the program, preliminary screening is normally performed using in vivo rodent models, thus an initial sample size of approximately 350 to 500 mg is required, unless prior knowledge of the compound's efficacy and toxicity is available. Directions for packaging and compound submission will also be provided prior to sample shipment.
NINDS recognizes the importance of confidentiality to the success of the ASP and its participants. Participation in the ASP begins only after the appropriate representatives from both the participant's organization and the NINDS sign the confidentiality agreement. This document defines the legal parameters for the partnership. All screening and other communication activities are performed in strict confidence to help safeguard the participant's intellectual property. Chemical structures are considered proprietary unless otherwise specified by the supplier. The only testing undertaken by the ASP is that agreed upon by participants in collaboration with ASP personnel. To further assure confidentiality, each newly submitted compound is assigned a unique ASP number code to be used in communications, tracking, and analysis. Screening personnel are blinded to both the structure and the source of submitted compounds, and screening results are provided exclusively to the participating supplier unless otherwise authorized.
Last updated January 26, 2015