Overcoming pressure ulcers with engineered hormones and stem cells

摘要 压力性溃疡（PU）是一种常见且痛苦的健康状况，特别是在老年人或老年人中。 身体受损PU可以影响美国至少300万成年人，并导致超过60，000名患者 每年都有PU死于这些溃疡不良的组织再生导致大量的发病率， 最关键的危险因素，特别是肢体截肢。原发性、周围神经病和内皮 功能障碍归因于PU。缺乏有效增强压力下组织再生的方案- 组织再生受损的患者。许多患者仍然面临截肢和死亡率增加。那里 是一种尚未满足但迫切的医学需求，以开发新的方案来增强压力性溃疡的愈合并预防 PU损伤愈合复发。我们提出这项研究来解决这个解决不好的问题。到 克服这一障碍，我们开发了一组“新型激素疗法”，稳定的嵌合白蛋白 （Alb）-或IgG Fc（Fc）-激素融合物（Alb-或Fc-激素）生物制剂和稳定的基于酶的生物制剂 纳米医学这些生物制剂或纳米药物的工程化稳定融合物将表现出延长的生物活性 和与野生型激素相比的体内功效。这些稳定的类似物可能有望用于治疗 压力溃疡本身。然而，我们的理由是，高度持久的激素融合生物制剂或缓释 纳米药物的配方（即，激素疗法）将是临床成功的关键，因为压力 溃疡通常需要长期治疗。我们的无毒激素疗法也会减少潜在的 全身副作用基于这种理解，我们假设，递送高度持久的Alb-或Fc- 激素融合生物制剂（新的激素疗法）将是一种有前途的策略，以提高组织 许多压力患者的再生。该项目旨在创建稳定的激素疗法和研究 它们单独或与成人脂肪干细胞（ASC）或诱导多能干细胞一起的治疗功效 （iPSC）来治愈慢性PU。具体目的：（目的1）产生具有强效和有效的抗肿瘤活性的新的激素治疗剂。 对角质形成细胞和内皮细胞（KECs）具有有效的生物活性。(Aim（2）研究小说的影响 在体外和啮齿动物模型中，激素治疗剂对来自ASC或iPSC的KEC重编程的影响。(Aim第三章 确定联合方案（新型激素方案加ASC或iPSC）在改善 使用PU啮齿动物模型进行PU组织再生并进行毒性研究。意义：我们的新疗法 使我们能够快速测试它们是否抑制PU，以改善PU患者。经过这项研究，我们 将确定安全和有效的抗PU方案准备用于临床前开发（例如，毒性和PK研究）， 这些问题将在第二阶段得到解决。我们希望这项工作能够有力地支持未来的SBIR第二阶段， 这项工作是一个有效的和一流的治疗PU。

Abstract Pressure ulcers (PUs) are a common and painful health condition, particularly among people who are elderly or physically impaired. PUs can affect at least 3 million adults in the U.S. and lead to more than 60,000 patients with PUs dying from these ulcers each year. Poor tissue regeneration causes substantial morbidity and is the most crucial risk factor for specific extremity amputation. Primarily, peripheral neuropathy and endothelial dysfunctions attribute to PUs. There is lacking regimens that effectively enhance tissue regeneration in pressure- damaged tissue regeneration patients. Many patients still face limb amputation and increased mortality. There is an unmet yet urgent medical need to develop novel regimens to enhance pressure-ulcer healing and prevent the recurrence of PU injury healing. We propose this research to tackle this poorly addressed problem. To overcome this obstacle, we have developed a group of “novel hormonal therapeutics,” stable chimeric albumin (Alb)- or IgG Fc (Fc)-hormones fusions (Alb- or Fc-hormones) biologics and stable hormones-based nanomedicines. These engineered stable fusions of biologics or nanomedicines will exhibit prolonged bioactivity and efficacy in vivo compared with wild-type hormones. These stable analogs may hold promise for treating pressure ulcers themselves. However, we reason that highly durable hormonal fusion biologics or slow-release formulas for nanomedicines (i.e., hormonal therapeutics) will be essential for clinical success because pressure ulcers usually require extended treatments. Our nontoxic hormonal therapeutics will also reduce potential systemic side effects. Based on this understanding, we hypothesize that delivering highly durable Alb- or Fc- hormone fusion biologics (novel hormonal therapeutics) will be a promising strategy to enhance tissue regeneration in numerous pressure patients. This project aims to create stable hormonal therapeutics and study their therapeutic efficacies alone or with adult adipose stem cells (ASCs) or induced pluripotent stem cells (iPSCs) to heal chronic PUs. Specific Aims: (Aim 1) Generate novel hormonal therapeutics with potent and effective bioactivity on keratinocytes and endothelial cells (KECs). (Aim 2) Investigate the effects of novel hormonal therapeutics on reprogramming of KECs from ASCs or iPSCs in vitro and in rodent models. (Aim 3) Determine the efficacy of combination regimens (novel hormonal regimens plus ASCs or iPSCs) in improving PU tissue regeneration using a PU rodent model and conduct toxicity studies. Significance: Our novel therapies allow us to rapidly test whether they suppress PUs specifically to improve patients with PUs. After this study, we will identify safe and effective anti-PU regimens ready for preclinical development (e.g., toxicity and PK studies), which will be addressed during Phase II. We expect this work strongly supports future SBIR Phase II to make this work to be an effective and first-in-class therapy for PUs.