DTRA: Research For The Future
2006 MEDICAL SCIENCE AND TECHNOLOGY CHEMICAL AND BIOLOGICAL DEFENSE TRANSFORMATIONAL MEDICAL TECHNOLOGIES INITIATIVE.
On April 22, 2003, the undersecretary of defense, acquisition, technology and logistics (USD(AT&L)) approved the Implementation Plan for the Management of the Department of Defense Chemical and Biological Defense Program (CBDP). The plan defines the roles and responsibilities and provides the implementation procedures for CBDP management. The CBDP provides for planning, programming, budgeting and execution of the chemical/biological/radiological/nuclear (CBRN) defense research, development and acquisition; programming and budgeting for CBD equipment, sustainment and training; establishing military requirements for CBRN defense; and test and evaluation of CBRN defense programs.
In line with these goals, the Defense Threat Reduction Agency (DTRA) has recently issued a broad agency announcement (BAA) to solicit proposals for the Department of Defense during Fiscal Year 2006 for the Medical Science and Technology (S&T) Chemical and Biological Defense Transformational Medical Technologies Initiative (TMTI). The DoD conducts a vigorous medical research and development program in chemical and biological defense with the goal of protecting the warfighter from disease and biological and chemical warfare agents. The CBDP seeks to develop countermeasures that can be brought into acquisition and fielded worldwide. These products have to be regulation-compliant, robust and highly effective at a reasonable cost. Successful candidates must demonstrate a clear path to regulatory approval, production, end-user utility and amenability in a military environment.
The BAA is focused on developing medical countermeasures to emerging threats, genetically engineered and nontraditional toxins, virulence factors and microorganisms as biological warfare (BW) threat agents. An important consideration is a more expedient approach and/or a shorter timeline to advanced development for a potential product. “It is anticipated that these countermeasures would include pretreatments (including vaccine enhancement technology), therapeutics and basic science to characterize the nature of the threat and identify key targets for intervention or disruption of these agents,” said Navy Captain Darrel Galloway, chief, Medical Division, Chemical/Biological Technologies Directorate, DTRA. “The agent classes that are to be focused on are: intra-cellular bacterial pathogens, hemorrhagic fever viruses and bioregulators.”
Approaches to the objectives for this area include studying the genetic diversity and pathogenicity of natural isolates, identifying common structural elements of specific agents or classes of agents, elucidating common virulence mechanisms (such as type III secretion proteins), identifying functional domains in toxins and virulence factors, and using this information to develop rapid and effective medical countermeasures protecting against genetically engineered or emerging BW threats.
OBJECTIVES
As with most research, there are three levels of exploration sought—basic, applied and advanced. According to Galloway, “This BAA is specifically for experimental and theoretical development of technologies for biological defense.”
BASIC RESEARCH
• Identify primary or common host pathways/ networks that respond to pathogenesis events for the initially selected pathogen groups and/or multiple-category A/B agents in order to evaluate potential intervention points for broad-spectrum therapeutic approaches.
• Develop systems biology tools to analyze complex biological functions at the level of gene expression, biochemical and metabolic pathways, and gene and protein structures to discover and validate novel biomarkers, drugs and future broad-spectrum drug targets.
• Exploit advances in genomics, proteomics, metabolomics (metabolic profiling) and systems biology studies to identify pathogenesis and host response pathways and networks for classes of pathogenic mechanisms.
• Develop in-silico methodologies to predict three-dimensional structure and comparative assessment of virulence moieties on important protein virulence molecules.
• Determine feasibility of redirecting host cellular response patterns that have been compromised by pathogen-directed shifts in pathways (e.g. overriding host apoptosis pathways, immune down-regulation, signal transduction agonists/antagonists, etc.) for protection and/or restoration of health.
APPLIED RESEARCH
• Develop computer-based technologies that enable the development of small-molecule medical countermeasure candidates based on structure/function analysis of either BW agent or host-response pathway target, in order to reduce the drug development timeline through parallel processing, tool interoperability and accessible information sources.
• Develop sophisticated ex-vivo, cell-based model systems to replicate target tissues (e.g., organ cultures, transplant models/ transgenic models) to replace animal models in the study of medical countermeasure bioactivity, efficacy and safety.
ADVANCED RESEARCH
• Drug discovery efforts in cutting-edge nucleic-acid-based therapies such as antisense and RNA-interference technology that targets common bacterial virulence or housekeeping genes (pathogenicity islands, quorum-sensing molecules, siderophores, etc.).
• Develop high throughput proteomic and metabolomic multiplex platforms to parallel-process multiple samples to generate informative, knowledge-based systems for target development and validation.
• Investigate new processes and systems for drug development to reduce drug development timelines through parallel processing of multiple drug candidates.
• Discover and develop new, or adapt existing, small-molecule compounds for therapeutic intervention against common pathogenesis pathways.
APPROACH
Through these research areas, DTRA is seeking optimum approaches to meet the scientific and technical objectives of the TMTI. Responses are expected in either one of two methods. The first will be individual research and development projects, and the other will use an integrated technical/management approach that encompasses the range of technical objectives within a long-term business arrangement.
DTRA is seeking single or multiple-year individual research and development projects that meet one or more of the specific objectives, particularly those that provide experimental and theoretical development of therapeutics for biological defense.
DTRA is also open to multiparties or other arrangements, such as a consortiums, teams or joint ventures, to integrate a broad array of technical solutions. Such an arrangement would enable the parties to complement each other’s unique capabilities and offer the best combination of performance, cost and schedule. It is critical that the research and development team be built around a systems integrator (SI) approach with strong program management in place. The SI will be responsible for the overall coordination of team direction, organization, and performance, and will take responsibility for the accomplishment of all milestones and the development of the final products, possibly to phase I of Invitational New Drug (IND) processes.
PROGRAM FUNDING
“A total of approximately $76 million is anticipated to be available for award under this BAA during FY 2006, with a potential additional funding of approximately $1.5 billion during FY 2007 through FY 2011,” said Galloway. While the earliest anticipated award is planned to occur in April 2006, the government may select for funding any full proposal or portions of a proposal at any time during FY 2006. ♦