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Posted: Nov 22, 2011
DARPA seeks to replace antibiotics with rapidly adaptable nanotherapeutics
(Nanowerk News) Through the U.S. Department of Defense's Small Business Innovation Research (SBIR) program, DARPA is currently soliciting research proposals to develop a platform capable of rapidly synthesizing therapeutic nanoparticles targeted against evolving and engineered pathogens (SB121-003: Rapidly Adaptable Nanotherapeutics; pdf).
Multiple classes of antibiotics exist, but the vast majority target only a handful of major bacterial functions, including bacterial protein production (such as translational blockade by anti-ribosomal agents), bacterial cell wall integrity, and genome integrity (DNA gyrase). The majority of these agents have been neutralized by bacterial selection and development of transmissible resistance, while the rest are prone to the same issues and may ultimately meet a similar fate. Ironically, the widespread use of antibiotics in agriculture and medicine has led to the emergence of "super strains" that are resistant to medical intervention.
Acquired resistance compromises our ability to fight emergent bacterial threats in injured warfighters and our military treatment facilities. For burn patients in particular, multidrug-resistant Acinetobacter calcoaceticus-baumannii complex (ABC) is a common cause of nosocomial infection, causing severe morbidity as well as longer hospital stays. Typically, antimicrobial resistant infections require a hospital stay three times as long and are in excess of four times as expensive. Therefore, new and innovative methods to control bacterial infection in the military health system are of critical importance.
Although broad spectrum antibiotics using a small molecule-based approach has been the historic solution, the time and money required to develop and obtain regulatory approval of new small molecule antibiotics has stifled production. For example, from 1983-1987 sixteen new antibacterial agents received FDA approval, while from 2003-2007 only four new agents were approved. Furthermore, many current and future small molecule agents would have limited applicability to engineered biological threats. Recent advances in nanomaterials, genome sequencing, nucleotide synthesis, and bioinformatics could converge in nanotherapeutics with tailored sequence, specificity, and function that can overcome earlier challenges. Collectively, these core technologies could permit the development of an innovative pharmaceutical platform composed of nanoparticles with tethered small interfering RNA (siRNA) oligonucelotides whose sequence and objective can be reprogrammed "on-the-fly" to inhibit multiple targets within multiple classes of pathogens.
This topic is focused on the development of a revolutionary rapidly adaptable nanotherapeutic platform effective against evolving and engineered pathogens. The biocompatible materials used to fabricate the nanoparticle should optimize cellular targeting, intracellular concentration, target sequence affinity, resistance to nuclease, and knockdown of target genes. The platform should leverage state-of-the-art genomic sequencing and oligonucleotide synthesis technologies to permit rapid programmability against evolving biologic threats.
Proposers should highlight the role of bioinformatics in the platform development and therapeutic design with an emphasis on using this information to: characterize pathogens that cannot be cultured; compare samples against a growing library of known pathogens; improve effectiveness of the recommended siRNA oligonucleotides; limit host transcriptome overlap and side effects; and potentially make recommendations on compassionate use in cases of life threatening pandemic infection.
Regulatory approval is key to successful use of the developed nanotherapeutics. Proposers should develop a regulatory approval plan for a representative nanotherapeutic as well as subsequent reiated nanotherapeutics produced by the good manufacturing practice (GMP) platform.
PHASE I: Define the component technologies necessary to develop a nanotherapeutic platform for the control of infection caused by evolving multi-drug resistant infection, including but not limited to nanomaterials; high fidelity DNA and RNA sequencing; siRNA oligonucleotide synthesis; evolving bioinformatics algorithms; and high throughput, reproducible biomaterials fabrication. Highlight new nanoparticle materials and functionalization that demonstrate high target entry, affinity and specificity with minimal side effects. Investigate relevant pathogen and molecular targets of interest for the military and civilian sectors that may be used for future proof of concept demonstrations. Develop and define the FDA regulatory approval plan for the initial nanotherapeutic, subsequent related nanotherapeutics, and eventual GMP platform. Phase I deliverables will include A detailed breadboard design of a Rapidly Adaptable Nanotherapeutic (RANT) platform.
PHASE II: Fabricate and iteratively refine the breadboard nanotherapeutic system. Fabricate a representative nanotherapeutic against a military relevant multidrug resistant organism. Iteratively refine the nanotherapeutic to suppress pathogen growth and/or toxicity. Validate the nanotherapeutic in a relevant small animal model. Phase II deliverables will include: 1. A representative nanotherapeutic that suppresses the growth and/or toxicity of a military relevant multidrug resistant organism. 2. A breadboard system capable of synthesizing nanotherapeutics against multidrug resistant pathogens. 3. Report detailing validation of the initial nanotherapeutic, GMP system design, and plan for regulatory approval.
PHASE III: Rapid identification and synthesis of nanotherapeutics targeted against evolving and engineered pathogens will improve care and mitigate biological threats. Development of an integrated platform system could be rapidly transitioned to pharmaceutical or medical device companies to enable an adaptable method for manufacturing therapeutic agents to target emerging threats on the battlefield or in both military and civilian hospitals. A prototype device may be capable of identifying and manufacturing therapeutic agents against multidrug resistant pathogens in military and civilian medical treatment facilities. A clear plan towards FDA approval for the therapeutic agent (or agents) and diagnostic/delivery platform will be in place, and additional testing to meet FDA requirements will be completed. Additional funding may be provided by DoD sources, but the awardee must also look towards other government or civilian funding sources to continue the process of translation and commercialization.
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