Exposure to ionizing radiation from a nuclear reactor accident or deliberate terrorist actions including the detonation of "dirty bombs" is a significant public health concern. The lung is particularly susceptible to ionizing radiation injury from external sources or inhalation of radioactive particles from radioactive fall-out. Radiation pneumonopathy can manifest with an acute radiation pneumonitis (ARS) and/or delayed effects of acute radiation exposure (DEARE) leading to progressive, often fatal pulmonary fibrosis. As prior warning of exposure is unlikely, medical countermeasures (MCMs) to mitigate radiation-pneumonopathy that can be given in mass-casualty situations many hours, days, and even months post-exposure are needed. Data from our proof-of-principle approach Phase I SBIR study using a well-established, targeted thoracic-radiation mouse model (C57BL/6), provided robust evidence supporting the effectiveness of KL4 surfactant (a proprietary, peptide-based synthetic surfactant) in mitigating both ARS and DEARE. In these experiments, KL4 surfactant was delivered intranasally twice daily for 2 weeks beginning 24 hrs post-irradiation. Preservation of lung function and reduced inflammation was observed in KL4 surfactant-treated mice at 2 and 4 wks post irradiation (i.e. mitigation of ARS), and importantly, reduction in subacute inflammation and pulmonary fibrosis (DEARE) at 4.5 months post exposure. Discovery Laboratories, Inc., a biotechnology company (small business concern) continues to evaluate KL4 surfactant (lucinactant) as a broad-spectrum, multi-use MCM against chemical, biological, radiological and nuclear threat agents targeting the lung. Given KL4 surfactant's lung-protective and immune-modulatory properties, ability to be delivered as an aerosol to spontaneously breathing subjects, and its robustness (resistance to inactivation by plasma proteins and oxidants present in the inflamed lung), the drug is an ideal MCM test candidate to treat radiation pneumonopathy. Moreover, the extensive preclinical and clinical safety/efficacy experience with KL4 surfactant (>1000 treated patients), and recent approval by the FDA for prevention of neonatal RDS should facilitate the regulatory approval of the drug as a MCM. Exogenous surfactants have never been evaluated for treating radiation pneumonopathy;thus our approach is novel. This SBIR Phase II proposal's Specific Aims are to conduct an in-depth evaluation of KL4 surfactant as a mitigator of radiation pneumonopathy using a more clinically-relevant scenario than that used in Phase I. Utilizing the same C57BL/6 thoracic irradiation mouse model in collaboration with Dr. Melpo Christofidou-Solomidou at the Univ. of Pennsylvania as in Phase I, we will now deliver KL4 surfactant in an aerosol formulation, in addition to evaluating three different treatment regimens that could be clinically relevant: (a) "early" treatment;(b) "early" plus "late";and (c) "late" only treatment.
Aim 1 evaluates whether aerosolized KL4 surfactant delivered as in (a) can prevent ARS;
and Aim 2, whether delivery of KL4 surfactant as in (b) and (c) can mitigate DEARE. The long-term objective is to obtain FDA approval of KL4 surfactant as a MCM for radiation pneumonopathy.

Public Health Relevance

Exposure to ionizing radiation and inhalation of radioactive particles from nuclear reactor accidents or deliberate terrorist actions is a significant health concern, since acute lung damage, or delayed, often fatal lung scaring can occur in exposed individuals and unprotected rescue workers. Discovery Laboratories, Inc., a biotechnology company, is testing its proprietary synthetic KL4 surfactant technology as a medical countermeasure (MCM) to treat radiation-induced lung injury. KL4 surfactant's lung-protective and anti- inflammatory properties suggest its potential as a broad-spectrum, multi-use MCM candidate. The proposed follow-on animal experiments should establish whether KL4 surfactant in an inhalation formulation should be further developed to protect the human lung and if successful, ultimately be approved as a MCM and be included in the Strategic National Stockpile for treating radiation exposure, an important goal of Project Bioshield.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
2R44AI102308-03
Application #
8782314
Study Section
Special Emphasis Panel (ZRG1-OTC-R (11))
Program Officer
Rios, Carmen
Project Start
2012-06-21
Project End
2017-07-31
Budget Start
2014-08-18
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
$999,999
Indirect Cost
Name
Discovery Laboratories, Inc.
Department
Type
DUNS #
171938970
City
Warrington
State
PA
Country
United States
Zip Code
18976