The overall objective of this project is to conduct IND-enabling drug development of a new small molecule radiomitigator based on the RP239 lead structure thru a partnership between the University of Tennessee and RxBio. Inc. This objective originates from a decade-long radiomitigator research that identified and validated the lysophosphatidic acid (LPA) G protein-coupled receptor (GPCR) subtype 2 (LPA2) as a therapeutic drug target for radiomitigation. RP239 is a specific small molecule agonist of LPA2. This proposal builds on our past experience and success developing octadecenyl thiophosphate (OTP) as a radiomitigator of the gastrointestinal acute radiation syndrome (GI-ARS). OTP licensed to RxBio Inc. was entered into the FDA regulatory pipeline under the sponsorship of BARDA in 2011. RP239 when applied +24h after LD90/8-10 (16.59 Gy) partial-body ?-irradiation with 5% bone marrow shielding reduced mortality of mice from the gastrointestinal acute radiation syndrome (ARS) by 72% (11/14 survival vs. 1/14 in placebo). RP239 and its analogs were also effective in reducing mortality due to the hematopoietic ARS. Importantly, when treatment was delayed to +48h post-total body irradiation, 50% of the mice survived in the RP239 treatment group compared to 21% in the placebo group. Its drug-like properties, combined with its specificity to the LPA2 receptor and lack of toxicity at therapeutic doses lead us to hypothesize that RP239 should be further evaluated as a potent radiomitigator of the mixed ARS elicited by high-levels of radiation. Our unique resources and experience with the development of OTP provide us with qualifications to take the RP239 lead on a development path that will qualify this new radiomitigator for fast tracking by the FDA under the animal rule.

Public Health Relevance

There are FDA-approved countermeasures available to deal with the looming threat of a nuclear accident like the one at Fukushima or explosion of a nuclear device, which necessitates the development of radiation countermeasures that are safe and effective when applied 24h or later after radiation injury. Our data with the small molecule RP239 show that it protects mice from very high levels of radiation with remarkable efficacy when applied +24-48 hours after radiation exposure. The goal of this project is the development of a new improved radiomitigator, designated RP239X, for priority or fast-track regulatory approval and inclusion in the Strategic National Stockpile.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AI107331-01
Application #
8573217
Study Section
Special Emphasis Panel (ZAI1-LGR-I (M1))
Program Officer
Dicarlo-Cohen, Andrea L
Project Start
2013-06-15
Project End
2018-05-31
Budget Start
2013-06-15
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$515,841
Indirect Cost
$168,482
Name
University of Tennessee Health Science Center
Department
Physiology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163