Agent X Still a Threat to Warfighters

Courtesy Photo | The figure above depicts the mechanism of actions of Insulin Growth factor -1 (IGF -1), a biological treatment for growth retardation in standard medical use. IGF -1 and other growth factors directly effect multiple steps in skeletal muscle hypertrophy and proliferation. The figure depicts IGF -1 restoration of the muscle end-plates, muscle fiber number and size leading to enhanced muscle contraction time in response to direct external stimuli. In brief, muscle tension box indicates enhanced muscle performance 14 and 28 days on IGF -1 treatment twice a day. Image courtesy of Dr. Feuerstein, JSTO.  

FORT BELVOIR, VIRGINIA, UNITED STATES

06.30.2016

Courtesy Story

Defense Threat Reduction Agency's Chemical and Biological Technologies Department

Fort Belvoir, Va. Engineered by the Canadian weapons program in 1939, Botulinum neurotoxins (BoNTs), once known as Agent X, are some of the most lethal toxins available. Although Canada did not produce a biological weapon using BoNTs, the United States, Japan, Germany, former Soviet Union and Iraq successfully engineered BoNTs for use as a weapon of mass destruction.

The U.S. renounced the use of chemical and biological weapons in 1969 and completed destruction of these weapons in 1972. However, other countries continued efforts to develop BoNT weapons.

The threat of weaponized BoNTs spurred researchers at the Defense Threat Reduction Agency’s Joint Science and Technology Office to lead an international consortium to pioneer effective medical countermeasures against the toxin.

Using tenants of Better Buying Power 3.0, a DoD initiative to achieve dominant capabilities through innovation, JSTO collaborated with the U.S. Army Medical Research Institute of Chemical Defense (USAMRICD), the Israel Institute for Biological Research (IIBR) and Hawaii Biotech, Inc., to tackle this complex issue.

By pooling resources, JSTO incentivizes productivity in industry and government, while creating a consortium aimed to develop the first novel small organic molecules BoNT inhibitors (SMIs) as well as provide proof-of-concept for regenerative medicine using insulin-like growth factor 1 (IGF -1).

BoNTs is a colorless, odorless and tasteless toxin derived from the Clostridium botulinum bacteria, and poses a significant threat to our warfighter community. The Centers for Disease Control and Prevention lists the toxin as a category A (highest risk to national security) agent. With the potential to be weaponized in a liquid, crystal or aerosol form, one gram of crystalline toxin, when disseminated properly, could kill one million people.

The rapid advances of biotechnology afford unprecedented capabilities to produce, disseminate and conceal BoNT from current diagnostic methods and escape contemporary anti-body treatments. Currently, BoNTs outpace contemporary medicine, making it difficult to effectively treat and decontaminate.

The consortium’s goal is to develop medical countermeasures, including SMIs and regenerative medicine. This transformational and unprecedented approach has taken advantage of recent BoNT science. Recent studies reveal fundamental features and discrete molecular mechanisms of BoNTs actions that afford rationale design and synthesis of potent site directed inhibitors of the toxin.

Recognizing the clinical sequel of BoNT actions led to the recognition that a regenerative medicine approach must be integral to combating the lingering, prolonged deaths associated with the toxin.

Equipped with this knowledge, the consortium embarked on synthesis of SMIs that potently and selectively inhibit BoNT -A, a specific strain of BoNT. Researchers anticipate that such
SMIs will instantly ‘choke’ the enzyme, inside the neuronal terminals where destruction of neurotransmission takes place. Thus, SMIs hold the promise to abort/attenuate toxins that induce respiratory arrest and death.

Simultaneous to the SMI effort, JSTO sponsored a “regenerative medicine” approach at USAMRICD laboratories, which also shows promising results. Using human, medically available growth factors, such as IGF -1, researches demonstrated enhanced recovery from severe BoNT -A intoxication in rat models.

These recent successes enable the JSTO-sponsored consortium to embark on in vivo pharmacokinetic and efficacy studies at IIBR. Studies will be conducted at IIBR based on the institute’s history of developing novel models that track respiratory functions following BoNT. The U.S. Food and Drug Administration has suggested potential avenues for accelerating the development timeline and fast tracking the studies.

Based on recent findings on BoNTs and the medical consequences, the JSTO consortium offers a highly complementary approach to the current treatment method of post systemic injections of antibodies.

The combination of the IGF -1 and SMI medical counter measures provides hope for the first time that BoNT intoxication can be reversed by small molecule inhibitors at the intra-neuronal site while concomitant treatment with muscle regenerative medical counter measures provides a fast and complete recovery, as shown by deterioration of respective clinical faculties. As the program enters into “animal rule” proof of efficacy studies, the JSTO team hopes to realize an investigational new drug candidate during fiscal year 2018.

POC: Dr. Giora Feuerstein; giora [e-mail]

• Date Taken: 06.30.2016
• Date Posted: 07.07.2016 09:25
• Story ID: 203271
• Location: FORT BELVOIR, VIRGINIA, US