Overcoming pressure ulcers with engineered hormones and stem cells

用工程激素和干细胞克服压疮

• 批准号: 10821146
• 负责人: Mickey Hu
• 金额: $ 29.59万
• 依托单位: LARIX BIOSCIENCE, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10821146
• 关键词: Address; Adipocytes; Adult; Affect; Albumins; Amputation; Animal Migration; Animals; Beds; Biological Assay; Biological Products; Blood Circulation; Cell Proliferation; Chimeric Proteins; Chronic; Circulation; Clinical; Data; Development; Diabetes Mellitus; Disease; Disease model; Drug Kinetics; Elderly; Endothelial Cells; Endothelium; Engineering; Exhibits; Face; Female; Fluorescence; Foot Ulcer; Functional disorder; Future; Half-Life; Health; Hormonal; Hormones; Image; Immunoglobulin G; Impairment; In Vitro; Injury; Intravenous; Limb structure; Lymphatic Endothelial Cells; Measures; Medical; Melanocyte stimulating hormone; Modeling; Morbidity - disease rate; Mus; Natural regeneration; Pain; Pathway interactions; Patients; Peripheral Nervous System Diseases; Persons; Phase; Plasma; Process; Proliferating; Quantum Dots; Recurrence; Regimen; Research; Risk Factors; Rodent; Rodent Model; Small Business Innovation Research Grant; Specificity; Survivors; Testing; Therapeutic; Time; Toxic effect; Treatment Efficacy; Ulcer; Vascular Endothelial Cell; Work; adipose derived stem cell; adrenomedullin; analog; angiogenesis; calcitonin receptor-like receptor; cell regeneration; clinical application; commercialization; decubitus ulcer; efficacy evaluation; endothelial dysfunction; endothelial regeneration; healing; improved; in vivo; induced pluripotent stem cell; keratinocyte; limb amputation; male; mortality; nanomedicine; novel; novel therapeutic intervention; novel therapeutics; optical imaging; peptide hormone; pre-clinical; preclinical development; pressure; prevent; programs; receptor; receptor-activity-modifying protein; side effect; stem cell differentiation; stem cells; success; tissue regeneration; tissue stem cells; wound

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.

抽象的 压疮 (PU) 是一种常见且令人痛苦的健康状况，尤其是老年人或老年人。 身体受损。 PU 可影响美国至少 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。组织再生不良会导致严重的发病率，并且是 特定肢体截肢的最关键危险因素。主要是周围神经病变和内皮细胞病变 功能障碍归因于 PU。缺乏有效增强压力下组织再生的方案 受损组织再生的患者。许多患者仍然面临截肢和死亡率增加的问题。那里 开发新的治疗方案以促进压疮愈合并预防压疮是一项尚未满足但紧迫的医疗需求 PU损伤愈合后复发。我们提出这项研究来解决这个尚未解决的问题。到 为了克服这个障碍，我们开发了一组“新型激素疗法”，稳定嵌合白蛋白 (Alb)-或 IgG Fc (Fc)-激素融合物（Alb-或 Fc-激素）生物制剂和基于稳定激素的 纳米药物。这些生物制品或纳米药物的工程稳定融合将表现出持久的生物活性 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 压疮本身。然而，我们认为高度持久的激素融合生物制剂或缓释制剂 纳米药物（即激素疗法）的配方对于临床成功至关重要，因为压力 溃疡通常需要长期治疗。我们的无毒激素疗法也将降低潜在的 全身副作用。基于这种理解，我们假设提供高度耐用的 Alb- 或 Fc- 激素融合生物制剂（新型激素疗法）将是增强组织的有前途的策略 许多压力患者的再生。该项目旨在创造稳定的激素疗法和研究 单独或与成体脂肪干细胞 (ASC) 或诱导多能干细胞一起使用的治疗功效 (iPSC) 来治愈慢性 PU。具体目标：（目标 1）产生具有有效且有效的新型激素疗法 对角质形成细胞和内皮细胞（KEC）具有有效的生物活性。 （目标 2）调查小说的影响 在体外和啮齿动物模型中，激素疗法对 ASC 或 iPSC 的 KEC 进行重编程。 （目标 3） 确定联合方案（新的激素方案加 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 让我们能够快速测试它们是否会专门抑制 PU 以改善 PU 患者的症状。经过这次研究，我们 将确定安全有效的抗 PU 方案，为临床前开发做好准备（例如毒性和 PK 研究）， 这将在第二阶段得到解决。我们期望这项工作能够有力地支持未来的 SBIR 第二阶段 这项工作将成为治疗 PU 的有效且一流的疗法。