Lipid Nanoparticles for Targeted Delivery of Enhanced Costimulation Blockade

用于增强共刺激阻断的靶向递送的脂质纳米颗粒

• 批准号: 8869242
• 负责人: Giorgio Raimondi
• 金额: $ 24.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8869242
• 关键词: Acute; Address; Adopted; Adverse effects; Affect; Antigen-Presenting Cells; Behavior; Biodistribution; Biological; Biological Assay; Biological Availability; CTLA4 gene; CTLA4-Ig; Cell physiology; Cells; Chronic; Clinic; Clinical; Data; Dendritic Cells; Development; Diabetes Mellitus; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug toxicity; Environment; FDA approved; Foundations; Graft Rejection; Graft Survival; Half-Life; Health; Heart Transplantation; Hypertension; Imaging Techniques; Immune; Immune system; Immunosuppression; Immunosuppressive Agents; Incidence; Infection; Inflammatory; Interdisciplinary Study; Intervention; Intestines; Life; Lipids; Lymphatic; Lymphatic System; Malignant Neoplasms; Mediating; Membrane; Mus; Natural Immunity; Operative Surgical Procedures; Opportunistic Infections; Optics; Oral; Organ Transplantation; Outcome; Pathology; Patients; Pharmaceutical Preparations; Preparation; Production; Property; Public Health; Quality of life; Regimen; Regulation; Research Design; Route; Signal Transduction; Skin; Solid; Solutions; Survival Rate; T-Cell Activation; T-Lymphocyte; Therapeutic Effect; Time; Translations; Transplant Recipients; Transplantation; Transplanted tissue; Trauma; Work; absorption; adaptive immunity; base; biomaterial compatibility; controlled release; cytokine; end stage disease; end-stage organ failure; heart allograft; immunoregulation; improved; in vivo; in vivo imaging; inhibitor/antagonist; innovation; mouse model; multidisciplinary; nanoparticle; nanotherapeutic; prevent; public health relevance; research clinical testing; research study; response; small molecule; synergism; targeted delivery; theories

 DESCRIPTION (provided by applicant): Solid organ transplantation is the therapy of choice for end-stage diseases, but the ensuing life-long use of immunosuppressive drugs compromises the quality of life and overall survival of these patients. The development of a treatment that minimizes the number of interventions, and associated side effects, would be transformative for this field. Clinical testing of the modulation of graft rejecting T lymphocytes through costimulation blockade (use of the biologic CTLA4-Ig, recently approved by the FDA) has shown improvements over the side effects of conventional immunosuppression, but has also shown unacceptably high rates of acute rejection episodes. This indicates that the initial view of activation of the rejection response was oversimplified and additional factors contribute to its modulation. Our ongoing experiments support the emerging theory that inflammatory cytokines (released during and after transplantation) neutralize the modulatory effect of CTLA4-Ig. We have discovered that short-term inhibition of the production and signaling of inflammatory cytokines, through the small molecule inhibitor Tofacitinib (Tofa), synergizes with CTLA4-Ig to prevent the activation of T cells and promotes transplant survival in a mouse model of heart transplantation. Due to the short in vivo half-life of Tofa, and the side effects associated with is chronic use, the clinical translatability of our approach hinges on realizing precise control over Tofa release and biodistribution, so to maximize its therapeutic effect. To achieve this, we propose to use an emerging class of nanoparticles for drug delivery: lipid-derived nanoparticles (LNp). In addition to their proven advantages with respect to biocompatibility and stability, LNp also have the unique ability to accumulate in the lymphatic system following administration and, if properly sized, they can cross biological barriers like skin (as indicated in our preliminary daa) or the intestinal membrane. We propose the hypothesis that LNp-mediated in vivo delivery of Tofa will result in transient, but controlled, localized modulation of the immune environment of a transplant recipient and will maximize the modulatory effect of CTLA4-Ig, realizing what we define "Enhanced Costimulation Blockade" (ECoB) and promoting long-term graft survival. This hypothesis will be addressed in the experiments of two Specific Aims: (1) to optimize the formulation of Tofa-LNp to maximize their impact on innate and adaptive immune cells responsible for rejection; and (2) to define the route of administration for optimal in vivo distribution of Tofa- LNp to achieve ECoB-mediated modulation of heart graft alloreactivity and promote long-term survival. Overall, these studies are designed to define the foundation for the development of a platform of intervention (LNp-based) for localized and safe immune-modulation that could be exploited to transform the treatment of transplant patients as well as further evolved to benefit patients with immune pathologies.

 描述(申请人提供)：实体器官移植是终末期疾病的首选治疗方法，但随之而来的终身免疫抑制药物的使用损害了这些患者的生活质量和总体生存。开发一种将干预次数和相关副作用降至最低的治疗方法，将对该领域产生革命性的影响。通过共刺激阻断(使用FDA最近批准的生物CTLA4-Ig)调节移植物排斥T淋巴细胞的临床测试显示，与传统免疫抑制的副作用相比，改善了，但也显示出不可接受的高急性排斥反应发生率。这表明最初关于排斥反应激活的观点过于简单化，其他因素参与了它的调节。我们正在进行的实验支持一种新的理论，即炎性细胞因子(在移植过程中和移植后释放)中和CTLA4-Ig的调节作用。我们发现，在小鼠心脏移植模型中，通过小分子抑制剂tofacitinib(TOFA)短期抑制炎性细胞因子的产生和信号传递，与CTLA4-Ig协同作用，防止T细胞的激活，并提高移植存活。由于Tofa在体内的半衰期较短，且与长期使用有关的副作用，我们的方法的临床可译性取决于实现对Tofa的释放和生物分布的精确控制，从而使其治疗效果最大化。为了实现这一点，我们建议使用一种新兴的纳米颗粒来给药：脂源性纳米颗粒(LNP)。除了在生物相容性和稳定性方面被证实的优势外，LNP还具有独特的能力，在给药后在淋巴系统中蓄积，如果大小合适，它们可以跨越生物屏障，如皮肤(正如我们初步的DAA所示)或肠膜。我们提出的假设是，LNP介导的TofA体内传递将导致移植受者免疫环境的短暂但可控的局部调节，并将最大化CTLA4-Ig的调节作用，实现我们所定义的增强共刺激阻断(ECOB)，促进移植物的长期存活。这一假设将在两个特定目标的实验中得到解决：(1)优化TOFA-LNP的配方，以最大限度地提高其对导致排斥反应的先天性和获得性免疫细胞的影响；(2)确定TOFA-LNP在体内的最佳分布途径，以实现ECOB介导的心脏移植物同种异体反应的调节，并促进长期存活。总体而言，这些研究旨在为开发一种局部和安全的免疫调节的干预平台(基于LNP)奠定基础，该平台可用于改变移植患者的治疗，并进一步演变为使患有免疫病理的患者受益。