NorLeu3-A(1-7): Enhanced Recovery of Radiation Burns

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DESCRIPTION (provided by applicant): Epithelial radiation injury can result in lesions from direct exposure or indirectly by damage to progenitors that contribute to healing. Healing is impeded by the effects of radiation which include reduced blood flow, injury to progenitors involved in epidermal healing, and increased susceptibility to infection resulting from damage to the bone marrow and immune system. We have shown that angiotensin peptides can rapidly promote wound healing as well as hematopoiesis, both of which are needed in healing burns that result from radiation blasts. We have found in pre-clinical studies that A(1-7) promotes tissue regeneration in animal models. NorLeu3-A(1-7), an analogue of A(1-7), was superior in wound healing to AII, A(1-7), and RegranexTM, the only FDA approved drug for this indication. Dr. Rodgers was recently awarded an SBIR Phase II grant to develop this peptide for topical application to treat chronic dermal wounds. Within the term of the SBIR grant, we have developed the optimal formulation that will provide the basis for the studies in this application, completed Investigation New Drug Application (IND)-enabling toxicology, obtained an IND from the US Food and Drug Administration, manufactured clinical supplies under Good Manufacturing Procedures and conducted Phase I clinical trials. This work is ongoing and will include initiation of a Phase II clinical trial and conduct of reproductive toxicology studies. These data will complement the objectives of this application. The development plan for this product in combined radiation and thermal injury (CRBI) includes (1) assessment of changes in expression of RAS receptors and components after irradiation followed by thermal injury to wild type and receptor knock out mice (2) determination of receptor-ligand interactions needed for optimal healing in CRBI; (3) testing of the efficacy of topical formulation of NorLeu3- A(1-7) currently optimized for chronic skin healing in rodent models of CRBI and (4) evaluation of the ability of topical formulations of NorLeu3-A(1-7) to increase progenitor number in a model of radiation-induced skin injury by radiation. This application will develop a product aimed at the mitigation of mortality arising from combined radiation and burn injuries and accelerate the healing of the thermal injury. With the threat of accidental or deliberate exposure of large populations to ionizing radiation and the potential for combined injuries, mitigation of side effects of such exposure that cause high degrees of morbidity and mortality is of importance.