Early Successes of DTRA’s Blood-Brain Barrier Program Suggest New Countermeasures

Courtesy Photo | Incorporation of flexible electronics into a human-derived blood-brain barrier model for real-time tracking of transport phenomena. Image courtesy of Bradley Ringeisen, Naval Research Laboratory, developed under DTRA contract.  

FORT BELVOIR, VA, UNITED STATES

07.25.2016

Courtesy Story

Defense Threat Reduction Agency's Chemical and Biological Technologies Department

Fort Belvoir, Va. One of the challenges in developing medical countermeasures for chemical and biological warfare agents is addressing the effects on the central nervous system (CNS).
Over the past year, the Defense Threat Reduction Agency’s Joint Science and Technology Office reinvigorated its lead role in addressing this challenge. They did this by standing up the fundamental research program, Understanding of the Blood-Brain Barrier (BBB) in Threat Environments, under science and technology manager Dr. Brian Pate.

The program aims to understand the effects of nerve agents and alphaviruses on the blood-brain barrier and find new transport pathways to deliver appropriate therapeutics into the CNS. The early successes of JSTO’s program allows researchers to better assess the risks of emerging threats while enhancing their ability to protect and treat warfighters from a broad range of chemical and biological threats.

Dr. Pate facilitated a discussion of the program and its early successes during the 2nd Annual Blood-Brain Barrier Conference of the World Preclinical Congress, generating significant interest from attendees.

DTRA’s program leverages several approaches to accomplish its goal. One approach centers around the development of correlated in silico, in vitro and in vivo models of the BBB, including in vitro models derived from human induced pluripotent stem cells incorporating three-dimensional architectures and soft electronic materials. These enable improved recapitulation of the human BBB as well as real-time tracking of transport phenomena. The Naval Research Laboratory, Harvard University, Johns Hopkins University, the University of Michigan and the University of Wisconsin are conducting this research as part of DTRA’s Understanding of the BBB in Threat Environments program.

Recently NRL scientists publicized the work, as presented in the figure (shown on Page 5), at the National Science Foundation’s Additive Manufacturing for Health Applications Conference, the National Materials and Manufacturing Board Meeting and to the U.S. National Committee on Theoretical and Applied Mechanics. In addition, NRL scientists will present additional findings at the Military Health System Research Symposium in August.

A second approach of the program spearheaded by the University of Michigan focuses on challenging these BBB models with libraries of nanoparticulates of varied physical-chemical properties such as size, morphology, surface chemistry and elastic modulus to understand the effect of these parameters in dictating entry into the CNS. The Bioengineering & Translational Medicine article, “Engineering of nanoparticle size via electrohydrodynamic jetting,” describes the establishment of a technological approach to compartmentalized nanoparticles with defined sizes in order to modulate cellular uptake.

Further, the University of Wisconsin is tackling a third approach to identify new transport pathways for entry into the BBB which focuses on the identification of more specific and rapid means to introduce medical countermeasures into the CNS.

The team produced an extensive library of human single-chain antibody fragments and identified several that are highly selective for BBB transport during recent in vitro and in vivo testing. In parallel, the team is exploring the engineering of new antibodies targeting a known BBB transport pathway mediated by the transferrin receptor, in order to improve the speed and selectivity of molecular uptake by this pathway for drug delivery purposes.

Additional approaches being pursued by the program focus on understanding and countering the effects of more specific insults to the BBB, including effects induced by nerve agent simulants and alphaviruses.

The nerve agent simulants work is being performed at Johns Hopkins University and the Sheba Medical Center while the alphavirus work is at Washington University, the University of Pittsburgh and the United States Army Medical Research Institute of Infectious Diseases. A variety of preliminary results obtained under these approaches revealed the time- and spatially-differential permeability of the BBB induced by Venezuelan equine encephalitis virus and paraoxon, and revealed a promising method to counter cellular death induced by the latter.

The team’s early successes resulted in several internal invention disclosures that are currently being prepared for patent application. These technological advances offer new hope for warfighters and medical personnel facing the risk of exposure to nerve agents or to neurotropic viruses such as alphaviruses.

Addressing the brain-damaging effects of such chemical and biological agents will leave warfighters with an improved ability to accomplish their missions, return to service and lead long and healthy lives in the face of the significant chemical and biological weapons threats.

POC: Dr. Brian Pate; [e-mail]

• Date Taken: 07.25.2016
• Date Posted: 07.25.2016 14:46
• Story ID: 204956
• Location: FORT BELVOIR, VA, US