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Pathogen Countermeasures

   

pathogen countermeasures logo The Pathogen Countermeasures program defied conventional wisdom by both developing and demonstrating revolutionary, broad-spectrum medical countermeasures against pathogenic organisms and/or their pathogenic products. The program pursued countermeasures versatile enough to eliminate biological threats — whether from natural sources or modified through bioengineering or other manipulations. Research areas included wide-spectrum countermeasures that target more than one pathogen, novel agents that stimulate body’s innate immune system, and host-oriented therapeutics that temporarily deny the pathogen use of the host’s cellular machinery.

Accomplishments included—

  • Development of an engineered, chimeric, double-stranded RNA (dsRNA) activated caspases (DACs) with broad-spectrum antiviral activity.
  • Development and clinical testing of CpG motifs for use as powerful innate immune activators. Proof of concept included the demonstration that addition of CpG to the AVA anthrax vaccine would yield a nearly nine-fold improvement in toxin neutralizing antibody, and at a significantly enhanced rate.
  • A novel target discovery technique now commonly referred to as “Random Homozygous Knock-Out" (RHKO), wherein both alleles of a mammalian gene are inactivated using antisense RNA strategies. Cells that survive exposure to toxins/pathogens as a result of RHKO are selected; and genes whose functional inactivation has led to disease resistance are identified, cloned, and validated as targets for pharmacological or immunological therapies aimed at interfering with toxin effects.
  • Discovery that inhibition of host gene TSG101, which regulates protein trafficking within the cell, also mediates the assembly and release (budding) of mature viral particles from the cell surface thereby affording a wide spectrum antiviral therapeutic.
  • Demonstration of phage derived protein therapeutics that specifically target, and kill, anthrax. These same phage derived proteins also formed the core of a new anthrax identification assay now in use within the U.S. laboratory response network.
  • Assembly of a set of scalable supercomputer hardware, software, and molecular databases for rapid, in silico identification of selective enzyme inhibitors, resulting in novel and effective countermeasures. This project, which has been transitioned to DoD, included a molecular database of more than 2 million drug-like, 3D chemical structures. Using this setup, a multidimensional structure of SARS proteinase was successfully predicted within 20 days of the genome publication, facilitating the design of anti-SARS drugs.
  • These and other results proved the concept that broad-spectrum countermeasures were indeed technically feasible. As such, this program laid the scientific foundation for the OSD/DTRA program, “Transformational Medical Countermeasures Initiative," which will further develop these and other broad-spectrum therapeutics to the stage of early clinical trials.

 

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