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

描述(申请人提供)：上皮辐射损伤可通过直接暴露或间接损害有助于愈合的祖细胞而导致损害。愈合受到辐射的影响，包括血流量减少，参与表皮愈合的祖细胞受到伤害，以及骨髓和免疫系统受损导致的感染易感性增加。我们已经证明，血管紧张素肽可以迅速促进伤口愈合和造血，这两者都是治愈辐射爆炸造成的烧伤所必需的。我们在临床前研究中发现，A(1-7)在动物模型中促进组织再生。NorLeu3-A(1-7)是A(1-7)的类似物，在伤口愈合方面优于AII，A(1-7)，以及FDA唯一批准用于这一适应症的药物RegranexTM。罗杰斯博士最近获得了SBIR第二阶段拨款，用于开发这种局部应用于治疗慢性皮肤伤口的多肽。在SBIR资助期内，我们开发了将为本申请的研究提供基础的最佳配方，完成了支持新药应用(IND)的毒理学研究，获得了美国食品和药物管理局(FDA)的IND，根据良好的制造程序生产了临床用品，并进行了第一阶段临床试验。这项工作正在进行中，将包括启动第二阶段临床试验和进行生殖毒理学研究。这些数据将补充本申请的目标。该产品用于放射和热联合损伤(CRBI)的开发计划包括：(1)评估野生型和受体敲除小鼠照射后RAS受体和成分的表达变化；(2)确定CRBI最佳愈合所需的受体-配体相互作用；(3)测试目前优化用于CRBI啮齿动物模型慢性皮肤愈合的局部制剂NorLeu3-A(1-7)的有效性；(4)评价NorLeu3-A(1-7)局部制剂在辐射致皮肤损伤模型中增加祖细胞数量的能力。这一应用将开发一种产品，旨在减轻辐射和烧伤复合损伤引起的死亡率，并加速热损伤的愈合。由于大量人口意外或故意暴露在电离辐射中的威胁以及合并伤害的可能性，减少这种暴露的副作用具有重要意义，这种副作用会导致高度的发病率和死亡率。

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.