Phase II year
2010
(last award dollars: 2014)
Phase II Amount
$3,278,253
A major instigator of radiation-induced pathology is cellular damage caused by reactive oxygen species formed in the first moments after exposure. Most therapeutic agents are free radical scavengers which must be present in high concentrations as exposure occurs, making their use as treatments problematic. In addition, the normal cell already has scavenger molecules present, such as glutathione. Glutathione accepts electrons from reactive electrophiles as part of the normal cellular defenses, but the resultant electrophilic glutathione conjugates still pose a threat to cellular integrity. Final elimination of risk then requires the transport and elimination of these reactive glutathione S-conjugates - a key function of RLIP76, a membrane-associated transport protein. Terapio has been testing RLIP76 as a systemic therapy for high-dose radiation poisoning. Preliminary studies in mice show that increasing cellular content of RLIP76 by systemic administration significantly increases survival even if the protein is administered AFTER radiation exposure, with a clear dose-response relationship between amount of RLIP76 administered and survival that extends to all but the highest exposure levels. Further, RLIP76 can be orally administered, increasing its ease of treatment. In order to move forward with clinical development, additional work regarding protein storage, stability, optimal dosing and schedule of administration is necessary. Further, although much is known about the protein's mechanism of action on a cellular level, organ-specific effects have yet to be determined. Therefore, this proposal will focus on three main areas. Specific Aim 1 will look at the stability of the protein under a variety of storage conditions to determine loss of activity and how that may affect recommended dosing in the field. Expanded studies of in vivo stability of the protein will be performed by following tissue levels of administered protein over time. Specific Aim 2 will enlarge understanding of the relationship between dose level, timing and schedule of administration and length of treatment in a mouse model. Specific Aim 3 will look at how RLIP76 affects specific organ toxicity from radiation and examine potential long term effects, again in a mouse model. The information obtained is necessary to plan an optimal treatment regimen for RLIP76 under different radiation release scenarios.
Public Health Relevance: RLIP76 is a naturally-occurring protein that can be given orally and counteract the effects of radiation poisoning even if given AFTER exposure occurs. This project will investigate the most effective dosing of the protein and how to optimize packaging for long term storage.
Public Health Relevance Statement: Development of RLIP76 as a Radiation Countermeasure: Project Narrative RLIP76 is a naturally-occurring protein that can be given orally and counteract the effects of radiation poisoning even if given AFTER exposure occurs. This project will investigate the most effective dosing of the protein and how to optimize packaging for long term storage.
Project Terms: Active Oxygen; Activities of Daily Living; Activities of everyday life; Acute; Address; Affect; Analysis, Data; Animals; Anthracyclines; Area; Assay; Autopsy; Bioassay; Biologic Assays; Biological Assay; Biosynthetic Proteins; Body Tissues; Carrier Proteins; Cell Death; Clinical; Clinical Paths; Data; Data Analyses; Development; Dose; Drug Formulations; ELISA; Effects of radiation; Effects, Longterm; Electrons; Enzyme-Linked Immunosorbent Assay; Excipients; Formulation; Formulations, Drug; Free Radical Scavengers; Future; Genome Instability; Genomic Instability; Glutathione; Glycine, N-(N-L-gamma-glutamyl-L-cysteinyl)-; Half-Life; Half-Lifes; Human; Human, General; Immunoblotting; In Vitro; Injury; Investigation; Laboratory Study; Length; Liposomal; Liposomes; Long-Term Effects; Mammals, Mice; Man (Taxonomy); Man, Modern; Measures; Membrane; Mice; Murine; Mus; Negative Beta Particle; Negatrons; Normal Cell; Organ; Organ Survival; Oxidative Stress; Oxygen Radicals; Pathology; Pharmacodynamics; Phase; Poisoning; Pro-Oxidants; Protein Cleavage; Proteins; Proteolysis; Protocols, Treatment; RGM; Radiation; Radiation Toxicity; Reactive Oxygen Species; Recombinant Proteins; Regimen; Reporting; Risk; SBIR; SBIRS (R43/44); SCHED; SYS-TX; Sampling; Schedule; Small Business Innovation Research; Small Business Innovation Research Grant; Specific qualifier value; Specified; Systemic Therapy; Testing; Therapeutic Agents; Time; Tissues; Transport Proteins; Transporter Protein; Treatment Protocols; Treatment Regimen; Treatment Schedule; Work; base; cohort; commercialization; daily living functionality; design; designing; drug development; effect, adverse, radiation; experiment; experimental research; experimental study; functional ability; functional capacity; gamma-L-Glu-L-Cys-Gly; gamma-L-Glutamyl-L-Cysteinylglycine; gene product; improved; in vivo; membrane structure; micronucleus; mouse model; necrocytosis; necropsy; oxidative damage; peripheral blood; poisoned; postmortem; protective effect; public health relevance; radiation effect; ray (radiation); reconstitute; reconstitution; research study; response; treatment planning; ward
