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

NorLeu3-A(1-7)：增强辐射烧伤的恢复

• 批准号: 8055215
• 负责人: KATHLEEN E. RODGERS
• 金额: $ 67.43万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-07 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055215
• 关键词: Adverse effects; Angiotensins; Animal Model; Award; Blast Cell; Blood flow; Bone Marrow; Burn injury; Cavia; Chronic; Clinical; Complement; Data; Dermal; Development; Development Plans; Dose; Drug Formulations; Epithelial; Evaluation; FDA approved; Grant; Healed; Hematopoiesis; Immune system; Infection; Injury; Investigation; Ionizing radiation; Knockout Mice; Lesion; Ligands; Modeling; Morbidity - disease rate; Mus; Peptides; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Population; Predisposition; Procedures; Radiation; Radiation Injuries; Recovery; Renin-Angiotensin System; Rodent; Rodent Model; Site; Skin; Small Business Innovation Research Grant; Topical application; Toxicology; United States Food and Drug Administration; Work; Wound Healing; analog; base; efficacy testing; healing; heat injury; irradiation; mortality; norLeu3-A(1-7); preclinical study; progenitor; radiation effect; radiation recovery; receptor; reproductive; time interval; tissue regeneration

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.

描述（由申请人提供）：上皮辐射损伤可直接暴露或间接损害有助于愈合的祖细胞而导致病变。愈合受到辐射影响的阻碍，包括血流量减少，参与表皮愈合的祖细胞受到损伤，骨髓和免疫系统受损导致对感染的易感性增加。我们已经证明血管紧张素肽可以快速促进伤口愈合和造血，这两者都需要愈合烧伤的辐射爆炸。我们在临床前研究中发现，A（1-7）促进动物模型的组织再生。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）和RegranexTM （FDA唯一批准用于该适应症的药物）。罗杰斯博士最近获得了SBIR二期资助，开发这种用于局部应用治疗慢性皮肤伤口的肽。在SBIR拨款的期限内，我们已经开发出了最佳配方，将为本申请中的研究提供基础，完成了研究新药申请(IND)-使毒理学，从美国食品和药物管理局获得了IND，根据良好生产程序生产临床用品，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。这些数据将补充本应用程序的目标。该产品在辐射和热联合损伤（CRBI）中的开发计划包括：(1)评估辐照后野生型和受体敲除小鼠热损伤后RAS受体和组分的表达变化(2)确定CRBI中最佳愈合所需的受体-配体相互作用；(3)测试目前在CRBI啮齿动物模型中优化的外用NorLeu3-A（1-7）制剂对慢性皮肤愈合的疗效；(4)评估外用NorLeu3-A（1-7）制剂在辐射引起的皮肤损伤模型中增加祖细胞数量的能力。该应用程序将开发一种产品，旨在减少辐射和烧伤合并造成的死亡率，并加速热伤的愈合。由于大量人口有意外或故意暴露于电离辐射的威胁，并有可能造成综合伤害，因此，减轻这种暴露造成高发病率和死亡率的副作用非常重要。

项目成果

Effects of combined radiation and burn injury on the renin-angiotensin system.

• DOI: 10.1111/j.1524-475x.2012.00867.x
• 发表时间: 2013-01
• 期刊: Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society
• 作者: Jadhav SS;Sharma N;Meeks CJ;Mordwinkin NM;Espinoza TB;Roda NR;DiZerega GS;Hill CK;Louie SG;Rodgers KE
• 通讯作者: Rodgers KE

Effect of combined radiation injury on cell death and inflammation in skin.

联合辐射损伤对皮肤细胞死亡和炎症的影响。

• DOI: 10.1007/s10495-015-1116-2
• 发表时间: 2015
• 期刊: Apoptosis : an international journal on programmed cell death
• 作者: Jadhav,SachinS;Meeks,ChristopherJ;Mordwinkin,NicholasM;Espinoza,TheresaB;Louie,StanG;diZerega,GereS;Rodgers,KathleenE
• 通讯作者: Rodgers,KathleenE