ABOUT THE PROGRAM OVERVIEW As part of its mission to reduce the burden of neurological disease, the National Institute of Neurological Disorders and Stroke (NINDS) established the Spinal Muscular Atrophy (SMA) Project: A Collaborative Program to Accelerate Therapeutics Development for SMA in late 2003. The goal of this program is to enable the development of therapeutic candidates for the treatment of SMA. This program is guided by experts from industry, academia, NINDS, and the U.S. Food and Drug Administration (FDA). With this guidance, we have established a multi-site drug discovery and development enterprise that conducts iterative cycles of chemical optimization and testing to identify compounds with improved effectiveness, safety, and pharmacokinetic characteristics. Through a contractor organization (SAIC), the SMA Project releases targeted solicitations to subcontract organizations that are qualified to perform the necessary activities and provide the resources outlined in the program plan. The drug discovery process is managed by a Lead Development Team (LDT) of consultants who have extensive pharmaceutical industry experience. The SMA Project represents a novel system for funding and monitoring of subcontracts. The Project successfully designed and used an accelerated receipt and review schedule for contract proposals. The Project has maintained a cost-effective and streamlined research and development program using research milestones to identify problems at early stages. This ensures efficient progress of R&D projects wherever possible and diversion of resources in the event of insurmountable problems. The heavy reliance upon industry-seasoned advisors and a focus on drug discovery make the SMA Project unique among NINDS-sponsored programs. It is viewed as a pilot project with potential benefits to other rare diseases, as well as other programs targeting SMA. DISCOVERY AND DEVELOPMENT OF NEW COMPOUNDS To identify new compounds with improved effectiveness, safety, and pharmacokinetic characteristics, the Steering Committee has designed a preclinical drug discovery and development effort that is modeled after those conducted by large pharmaceutical companies. Because pharmaceutical companies tend to focus their drug discovery and development efforts on diseases with large patient populations, this approach is generally not applied to SMA and other rare diseases. Compounds that increase the level of Survival Motor Neuron (SMN) Protein in cultured cells have been identified through the efforts of private foundations, academia, and industry and reviewed by the NINDS Therapeutic Advancement Program for Spinal Muscular Atrophy (TAP-SMA). These compounds represent potential leads that may be developed into drugs for clinical testing. To focus on unmet needs and increase the likelihood of success, the SMA Project drug discovery and development effort begins at the stage of optimizing existing active compounds.
The SMA chemists use medicinal chemistry and structure-activity-relationship (SAR) analysis methods to prepare chemical analogs of the lead compounds – new compounds with structures that are slightly modified. After testing in suitable assay systems, compounds found to be more effective than the original lead compounds are further modified, in iterative cycles, until maximum attainable bioactivity is achieved and known toxicities are minimized. We then test improved compounds in additional cellular and animal models for beneficial activities and drug like properties. If required, additional structural modifications can be introduced to improve upon a compound’s safety and pharmacologic profile. Once a candidate drug with all of the desired characteristics is identified, rigorous preclinical safety and pharmacokinetic studies are conducted to support preparation of an Investigational New Drug Application (IND) for human testing that will be submitted to the FDA. If the IND is successful, first-time-in-human testing can then begin. Because there are other NINDS-sponsored programs for advancing clinical development of investigational drugs, the SMA Project’s drug development effort concludes with preparation and submission of an IND.
COMPOUNDS AVAILABLE FOR RESEARCH COLLABORATIONS The SMA Project will make a subset of compounds available to researchers for in vitro testing under a Material Transfer Agreement (MTA). These early-stage, non-clinical compounds are active in assays of translational read through and therefore may be of interest to researchers with established read through assays related to diseases caused by nonsense mutations. For more information, please contact Lydia Munger, NINDS at mungerl@ninds.nih.gov. PROJECT STRUCTURE To duplicate the drug discovery and development capabilities of a large pharmaceutical company, the SMA Project has assembled a core group of collaborating organizations through various subcontracts. The prime contractor, SAIC, serves as a resource center for subcontractors and provides other management and administrative services to NINDS in support of the SMA Project.
Project Testing Funnel The SMA Project operates under a multi-tiered system for synthesis and testing of compounds. This system has been called the “testing funnel” because the number of compounds decreases as the testing advances. The first part of the testing funnel is an iterative process of new compound synthesis and testing that requires extensive communication and collaboration between the medicinal chemistry contractors and the in vitro screening contractors. Compounds that are sufficiently improved through these cycles move down the funnel for more advanced testing. The most promising compounds are tested for solubility, stability and other drug-like properties. Compounds that do not show significant issues in this stage advance to animal testing. Successful compounds then advance to late stage preclinical development and testing to predict human safety. As compounds move down the funnel, new compounds can feed in and are optimized at the top, identifying additional compounds for further testing. ABOUT SAIC SAIC is the nation’s largest employee-owned research and engineering company. As the prime contractor for the SMA Project, SAIC supports the NINDS in the management of all aspects of this program. These activities include (1) soliciting research proposals and convening panels of scientific experts for proposal review, (2) awarding research subcontracts, and (3) monitoring the course of subcontracted research projects and working with funded investigators to achieve performance milestones. SAIC serves as a resource center for subcontractors and provides other management/administrative services to NINDS in support of the SMA Project. |
For more information on the SMA Project, please e-mail This site is best viewed with Netscape 7.2 or Internet Explorer 6.0. Both are available for free download (www.netscape.com and www.microsoft.com). Some functionality will be lost when viewing this website with older versions of the web browsers. Home • About the Program • Solicitations • Advisory Committees • Last updated: February 27, 2008 This site is maintained for a specific SAIC project or contract. |
