DoD STTR 23.C BAA

Active
No
Status
Closed
Release Date
August 23rd, 2023
Open Date
September 20th, 2023
Due Date(s)
October 18th, 2023
Close Date
October 18th, 2023
Topic No.
DHA23C-002

Topic

Exosome Loaded Antibiotics for Bacterial Wound Infections

Agency

Department of DefenseN/A

Program

Type: STTRPhase: Phase IYear: 2023

Summary

The Department of Defense (DoD) is seeking proposals for the development of antibiotic-loaded exosomes for topical application on wounds for prophylaxis or adjunct treatment indications. The objective is to address the increasing mortality rates caused by multidrug-resistant bacterial infections in wounded patients. The topic focuses on the use of exosomes, nanoscale vesicles optimized for intercellular communication, to transport antibiotics to target cells and promote wound healing. The Phase I of the project will involve exosome formulation with a broad or narrow spectrum antibiotic, with a focus on reproducibility, scalability, and stability. Phase II will include pre-clinical evaluation of the antibiotic-loaded exosome using in vitro and animal wound models. The deliverable for this phase will be an antibiotic-loaded exosome that demonstrates safety and efficacy. Phase III will involve in vivo and human research to obtain FDA approval, with potential funding opportunities from various programs. The use of a topical antibiotic for ESKAPE pathogens would have immediate utility in both military and civilian settings. The solicitation is closed, and more information can be found on the DoD SBIR website.

Description

OUSD (R&E) CRITICAL TECHNOLOGY AREA(S): Military Infectious Disease

OBJECTIVE: The objective of this topic would be to develop antibiotic loaded exosomes for topical application on wounds for prophylaxis or adjunct treatment indications.

DESCRIPTION: Multidrug-resistant bacterial infections increase mortality rates in wounded patients and are becoming a public health concern for both military and civilian patients worldwide.1 As current antimicrobial therapies continue to lose efficacy against these pathogens, new countermeasures must be identified to maintain sufficient control of these infections. Among MDR bacteria, the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Entrobacter spp.) have been identified as particularly problematic pathogens that complicate wounds of U.S. military casualties.2

Topical application of antibiotics have long been evaluated as a potential route of administration as an adjunct or to prevent wound infections. In addition to the logistical advantages and ease of use of a topically applied antibiotic therapeutic, this route of administration affords the opportunity to decrease systemic absorption minimizing potential systemic toxicity that is common among many antibiotics given intravenously or orally to treat ESKAPE organisms. While its use in the surgical arena has demonstrated benefit, the efficacy of topical antibiotics in the field has been met with challenges such as poor tissue penetrance and local contact dermatitis side effects. A topical antibiotic product that could overcome these issues while demonstrating efficacy would have significant utilization potential as a prolonged field care tool as well as in the hospital setting. Current Tactical Combat Casualty Care Guidelines recommend the use of intravenous ertapenem for wound infections in soldiers that cannot take oral medications.3 While ertapenem’s broad spectrum of activity and bacteriocidal activity make it a highly effective antibiotic, its systemic use as a prophylactic therapeutic, especially in the prolonged field care setting, create an ideal situation for resistance development. A topical ertapenem with similar efficacy in preventing infections would offer improvements in stability, storage, ease of use, decrease risk of resistance and dosing error. It could be utilized by medics or physicians at any level of care in the deployed setting.

Extracellular vesicles (EVs) are nanoscale, lipid bilayer delimited vesicles that serve as the fundamental intercellular communication system. As such, these vesicles are optimized to transport biomolecular cargo (e.g., amino acids, nucleic acids, small molecules) throughout biological systems. A subset of EVs called exosomes feature specific receptors and proteins that decorate the lipid bilayer of the vesicle and enable rapid uptake into target cells and signal for efficient processing of the delivered cargo. By themselves, exosomes have exhibited wound healing properties demonstrating free radical scavenging to enhance cell survival, recruitment and support of local tissue progenitor cells to rebuild tissue and promotion of neoangiogenesis to restore blood supply.4 Exosomes loaded with an antibiotic would provide a safe, targeted topical approach to treating or preventing wound infections. Repurposing already approved antibiotics will allow for a quicker regulatory pathway.

PHASE I: This phase will focus on exosome formulation with a broad spectrum antibiotic that could be used for prophylaxis topically on wounds or a narrow spectrum antibiotic targeted as an adjunct treatment for a multi-drug resistant ESKAPE pathogen. The exosome should be a reproducible, sterile, easily re-constituted and scalable product. Exosome size should be relatively uniform ranging from 100-400nm. The product should be stable at room temperature. The company should have or be able to develop a process through which maximum drug loading efficiency can be achieved while maintaining the integrity of the exosomes. They should be able to scale this process to a degree in which sufficient doses could be provided for clinical use. Appropriate quality control checks The deliverables of this phase will be the manufacturing and quality control reports as well as a finished Current Good Manufacturing Practice (cGMP) product available for future use.

PHASE II: This phase will focus on pre-clinical evaluation of the antibiotic loaded exosome. Initial in vitro or ex vivo screening assays can be performed to further screen and refine prototypes. An in vitro biofilm model should be included with these assays. The next stage would involve evaluation of the exosome loaded antibiotic on an animal wound model. The wound model should be validated against whatever pathogen is to be tested against or prevented. In addition to safety and efficacy endpoints it should include a pharmacokinetic analysis to determine systemic exposure levels. End points such as time to wound closure, weight change, bacterial burden and clinical observations should be included. The deliverable for this phase would be an antibiotic loaded exosome that demonstrated safety and efficacy in a validated wound animal model with limited systemic exposure.

A regulatory strategy that reflects a clinical Target Product Profile (TPP) will need to be developed during this phase. This TPP should include information related to desired formulation, excipients, stability, quality control measures and manufacturing considerations. The regulatory strategy should include relevant in vitro release test and in vitro permeation test recommendations, small and large animal toxicology and pharmacokinetic/pharmacodynamics studies and plans for pre-Investigational New Drug FDA meetings.

PHASE III DUAL USE APPLICATIONS: This phase would focus on in vivo and human research needed to obtain FDA approval. Starting with dose ranging and animal toxicology studies and progressing to the first in human Phase 1 study. Similar exosome products have already undergone Phase 1 studies and by using already FDA approved antibiotics with a known safety profile the regulatory pathway may be shorter than traditional new molecular entities. Funding for further development efforts could be sought from such programs as the Joint Warfighter Medical Research Program, Biomedical Advanced Research and Development Authority or Medical Technology Enterprise Consortium. Once FDA approved, the use of a topical antibiotic that can be used to treat ESKAPE pathogens would have immediate utility and interest from civilian surgical centers for post-operative care and tertiary care inpatient and intensive care units as an adjunct for skin/wound infections.

REFERENCES:

  1. Calhoun JH, Murray CK, Manring MM. Multidrug-resistant organisms in military wounds from Iraq and Afghanistan. Clin Orthop Relat Res. 2008 Jun;466(6):1356-62. doi: 10.1007/s11999-008-0212-9. Epub 2008 Mar 18. PMID: 18347888; PMCID: PMC2384049.
  2. Katrin Mende, PhD, Kevin S Akers, MC, USA, Stuart D Tyner, MSC, USA, Jason W Bennett, MC, USA, Mark P Simons, USN, MSC, Dana M Blyth, USAF, MC, Ping Li, MS, Laveta Stewart, MSc, MPH, PhD, David R Tribble, MD, DrPH, Multidrug-Resistant and Virulent Organisms Trauma Infections: Trauma Infectious Disease Outcomes Study Initiative, Military Medicine, Volume 187, Issue Supplement_2, May-June 2022, Pages 42􀍴51, https://doi.org/10.1093/milmed/
  3. Committee on Tacticle Combat Casualty Care. Tactical Combat Acsualty Care Guidelines for Medical Personnel. 15 December 2021. https://books.allogy.com/web/tenant/8/books/b729b76a-1a34-4bf7-b76b-66bb2072b2a7/. Accessed 17 May 2023.
  4. Shi A, Li J, Qiu X, Sabbah M, Boroumand S, Huang TC, Zhao C, Terzic A, Behfar A, Moran SL. TGF-β loaded exosome enhances ischemic wound healing in vitro and in vivo. Theranostics. 2021 Apr 30;11(13):6616-6631. doi: 10.7150/thno.57701. PMID: 33995680; PMCID: PMC8120220

KEYWORDS: Exosomes, topical antibiotics, multi-drug resistant organisms, bacterial infections, wound infections, ESKAPE pathogens