Radiation-induced production of pro-inflammatory and pro-fibrotic cytokines results in chronic and irreversible damage to the lungs. To date, no agent has demonstrated a sufficient safety profile to be utilized as a clinical drug for mitigating damage from exposure to radiation from accidental or terroristic nuclear events. Consequently, there is a great need for new, mechanistically-targeted drugs that can be utilized to mitigate radiation poisoning of humans following unintended exposure. Many studies have implicated sphingolipid metabolism as a critical mediator of inflammatory and fibrotic processes. Inflammatory and pro-fibrotic cytokines produced by radiation exposure (e.g. TNF? and TGF?) activate sphingomyelinases and ceramidases to produce sphingosine, which is phosphorylated by sphingosine kinases (SK1 and SK2) to produce sphingosine 1-phosphate (S1P). It is established that SK activation and production of S1P are essential for signaling responses to inflammatory cytokines, including their ability to induce adhesion molecule expression via activation of NF?B. Similarly, collagen synthesis in response to TGF? is dependent on S1P production by SKs. Therefore, SKs are rational new targets for drugs that attenuate damaging inflammation and fibrosis. Apogee Biotechnology Corporation has identified the first orally-available SK inhibitors with activity in vitro and in vivo. The lead SK2 inhibitor, designated as ABC294640, has antitumor and anti-inflammatory activities in several in vivo models, while exhibiting very low toxicity to the animal. Our Preliminary Studies indicate that treatment of mice with ABC294640 protects against toxicity from total body or abdominal irradiation when the compound is given either pre-exposure or post-exposure. We hypothesize that suppression of SK2 activity by ABC294640 will mitigate pulmonary fibrotic damage from exposure to ionizing radiation. To establish justification for moving ABC294640 toward clinical trials for radiomitigation, we will conduct the following Specific Aims: 1) To determine the mechanism for ABC294640 protection against cytokine-induced fibrotic responses in cultured human fibroblasts;and 2) To characterize the ability of ABC294640 to protect against pulmonary fibrosis from thoracic irradiation. These studies will provide the experimental validation needed to justify future confirmatory studies in non- human primates, and ultimately clinical trials in humans.

Public Health Relevance

Exposure to ionizing radiation, which can occur through accidental or terroristic nuclear events, causes damage to a variety of organs including the lungs because of chronic inflammation and fibrosis. We have developed an orally-available inhibitor of the enzyme sphingosine kinase-2 that has anti-inflammatory activity in several animal models. We will examine the effects of this compound in mice to determine its ability to reduce radiation-induced lung damage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
1R43AI098309-01A1
Application #
8455896
Study Section
Special Emphasis Panel (ZRG1-OTC-R (11))
Program Officer
Rios, Carmen
Project Start
2013-01-07
Project End
2014-12-31
Budget Start
2013-01-07
Budget End
2013-12-31
Support Year
1
Fiscal Year
2013
Total Cost
$300,000
Indirect Cost
Name
Apogee Biotechnology Corporation
Department
Type
DUNS #
095628348
City
Hummelstown
State
PA
Country
United States
Zip Code
17036