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

描述（由申请方提供）：上皮辐射损伤可因直接暴露或通过损伤有助于愈合的祖细胞而间接导致病变。辐射的影响阻碍了愈合，包括血流量减少，对参与表皮愈合的祖细胞的损伤，以及对骨髓和免疫系统损伤引起的感染的易感性增加。我们已经表明，血管紧张素肽可以迅速促进伤口愈合以及造血，这两者都是由辐射冲击波引起的愈合烧伤所需要的。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。NorLeu 3-A（1 -7）是A（1-7）的类似物，在伤口愈合方面上级AII、A（1-7）和RegranexTM，后者是FDA批准的唯一用于该适应症的药物。Rodgers博士最近获得了SBIR第二阶段资助，用于开发这种局部应用于治疗慢性皮肤伤口的肽。在SBIR资助的期限内，我们开发了最佳配方，为本申请中的研究提供基础，完成了新药研究申请（IND）-使能毒理学，从美国食品药品监督管理局获得了IND，根据良好生产程序生产临床供应品，并进行了I期临床试验。这项工作正在进行中，将包括启动II期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。该产品在辐射和热损伤联合（CRBI）中的开发计划包括（1）评估野生型和受体敲除小鼠辐射后热损伤后RAS受体和组分表达的变化（2）确定CRBI最佳愈合所需的受体-配体相互作用;（3）在CRBI的啮齿动物模型中测试目前针对慢性皮肤愈合优化的NorLeu 3- A（1-7）的局部制剂的功效，和（4）评价NorLeu 3-A（1-7）的局部制剂的能力以增加辐射诱导的皮肤损伤模型中的祖细胞数量。该申请将开发一种产品，旨在减轻辐射和烧伤联合造成的死亡率，并加速热损伤的愈合。由于大量人口意外或故意受到电离辐射的威胁以及可能造成复合伤害，因此减轻这种造成高发病率和死亡率的照射的副作用至关重要。

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.