Inhaled Fasudil and DETA NONOate CAR-Targeted Liposomes for PAH

吸入法舒地尔和 DETA NONOate CAR 靶向脂质体治疗 PAH

• 批准号: 10274778
• 负责人: Fakhrul Ahsan
• 金额: $ 129.13万
• 依托单位: VASCULAR BIOSCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10274778
• 关键词: Address; Admixture; Adult; Affect; Affinity; Age; Animal Model; Animals; Arteries; Attention; Biological Assay; Blood; Blood Circulation; Blood Pressure; Blood Vessels; Cardiomegaly; Catheters; Child; Chronic; Combined Modality Therapy; Continuous Intravenous Infusion; Cyclic Peptides; Data; Deet; Development; Devices; Diagnosis; Disease; Disease Progression; Dose; Drug Delivery Systems; Drug Kinetics; Edema; Encapsulated; Endothelin Receptor Antagonist; Ethnic group; Formulation; Foundations; Gender; HIV; Heart failure; Homing; Hypertrophy; Hypoxia; Individual; Industry; Infusion procedures; Inhalation; Inhalation Drug Administration; Inhalation Therapy; Injections; Intravenous; Left; Legal patent; Liposomes; Long-Term Effects; Lung; Lung Transplantation; Malignant Neoplasms; Manufacturer Name; Medical; Modality; Modeling; Morbidity - disease rate; Myocardial dysfunction; Newborn Infant; Nitric Oxide; Nitric Oxide Donors; Obstruction; Oral; Oral Ingestion; Pathway interactions; Patient-Focused Outcomes; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology Study; Pharmacotherapy; Phase; Physiological; Plasma; Pre-Clinical Model; Prostaglandins I; Publishing; Pulmonary artery structure; Quality of life; Race; Rare Diseases; Rattus; Records; Research Personnel; Rho-associated kinase; Right ventricular structure; Safety; Scientist; Sensitivity and Specificity; Series; Sickle Cell Anemia; Specificity; Stroke; Symptoms; System; Systemic Scleroderma; Systemic blood pressure; Therapeutic; Therapeutic Effect; Time; Toddler; United States; Vascular remodeling; Vasodilation; Vasodilator Agents; Veterans; Woman; acute toxicity; analog; arterial remodeling; base; clinical translation; commercialization; common treatment; drug discovery; drug inhalation; experimental study; exposure route; fasudil; genotoxicity; heart function; hemodynamics; high risk; improved; inhibitor/antagonist; innovation; kinase inhibitor; liver injury; men; mortality; nanocarrier; novel; phosphodiesterase V; pre-clinical; pressure; prevent; pulmonary arterial hypertension; response; rho; side effect; subcutaneous; targeted treatment

Pulmonary arterial hypertension (PAH) affects ~15-50 individuals per million and claims ≥20,000 lives annually in the United States. It affects every ethnic group, race, age and gender, and devastates high-risk patients afflicted with HIV, systemic sclerosis, and sickle cell disease. The disease affects more women than men; adult PAH patients do not live more than five years after the diagnosis. PAH even affects newborn infants and toddlers: PAH-afflicted children do not survive past their second birthday, if left untreated. Current medications fail to reduce mortality, extend survival time, or enhance patient quality of life. Many patients do not respond to existing oral and inhaled anti-PAH drugs; thus, they must receive a continuous intravenous infusion of prostacyclin analogs, or undergo lung transplantation. Unlike the “emperors of maladies” (cancer and stroke), PAH has not received much attention from the drug-discovery establishment, so the progress toward medication development and long-term management of this “orphan” disease has been minimal. Since PAH affects only a relatively small number of patients, pharmaceutical manufacturers have not made it a priority to find a cure for PAH, a disease that was first described in the 1950s. In this project, we propose to develop a targetable and inhalable formulation of fasudil, a rho-kinase inhibitor, and DETA NONOate (DN), a nitric oxide (NO) donor. We will develop this combination therapy by encapsulating both drugs, fasudil and DN, in liposomes modified with a cyclic peptide, CAR (CARSKNKDC), which accumulates preferentially in hypertensive pulmonary arteries. In a series of studies, we have demonstrated that CAR-modified liposomes containing fasudil and DN reduce the mean pulmonary arterial pressure (mPAP), and this ameliorates various features of pulmonary arterial remodeling. In this Fast-Track application, we will evaluate the potential for the clinical translation and commercial development of our targeted liposomal formulation-based combination therapy for PAH. In Phase I, we will study the effect of the long-term administration of the inhaled CAR- liposomal formulation of fasudil-plus-DN on pulmonary hemodynamics, lung remodeling, and right ventricle (RV) hypertrophy, and determine the sensitivity and specificity of assays for detecting nanogram levels of fasudil and NO in plasma. In Phase II, we will conduct studies to determine the dose-response, pharmacokinetics and safety of the formulations. The proposed studies will lay the foundation for an FDA IND application and clinical translation, and will establish the CAR-liposomes of fasudil-plus-DN as a novel and inhalable therapeutic option for PAH patients that will: a) specifically target the hypertensive pulmonary vasculature, and b) provide synergistic therapeutic benefits through both the Rho A/Rho kinase and NO donor pathways, without the additive adverse side effect of systemic vasodilation. Our approach is innovative, because we will determine the chronic efficacy of a targeted two-drug inhalation therapy for PAH. We have a robust commercialization plan in place, our CAR-modified formulation will be protected by a patent for CAR peptide, and we have a team of investigators comprised of clinicians, statisticians, peptide chemists, lung biologists, industry veterans and a pharmaceutical scientist. Importantly, we propose to address an unmet medical need by developing an effective drug therapy for an under-investigated and devastating disease.

肺动脉高压（PAH）影响约15-50个个人，每年夺取≥20,000人的生活 在美国。它影响每个种族，种族，年龄和性别，并破坏高风险患者 患有艾滋病毒，全身性硬化症和镰状细胞病。这种疾病影响女性的人数多于男性。成人 诊断后的PAH患者的寿命不超过五年。 PAH甚至会影响新生婴儿， 幼儿：如果没有治疗，则由PAH的孩子在第二个生日过后无法生存。当前的药物 无法降低死亡率，延长生存时间或提高患者生活质量。许多患者没有回应 现有的口服和吸入抗PAH药物；因此，他们必须接受连续的静脉输注 前列环蛋白类似物或进行肺移植。与“疾病皇帝”（癌症和中风）不同， PAH并没有从毒品发现机构受到太多关注，因此 这种“孤儿”疾病的药物开发和长期管理至少。自PAH以来 仅影响相对较少的患者，药物制造商并未将其优先考虑 找到一种治疗PAH的方法，PAH是1950年代首次描述的一种疾病。在这个项目中，我们建议开发 Fasudil，Rho-kinase抑制剂和DETA NONOATE（DN）的靶向和吸入公式，一氧化氮 （否）捐助者。我们将通过将两种药物Fasudil和dn封装在这种联合疗法中 用环状肽，CAR（CARSKNKDC）修饰的脂质体，优先积聚 高血压肺动脉。在一系列研究中，我们证明了汽车改性的脂质体 含有Fasudil和DN降低平均肺动脉压（MPAP），这可以改善各种 肺动脉重塑的特征。在此快速轨道应用程序中，我们将评估 基于脂质体配方组合的临床翻译和商业开发 PAH的治疗。在第一阶段，我们将研究遗传性的长期给药的影响 Fasudil-Plus-DN的脂质体配方在肺血液动力学，肺部重塑和右心室 （RV）肥大，并确定检测纳米图水平的测定的灵敏度和特异性 Fasudil，在等离子体中没有。在第二阶段，我们将进行研究以确定剂量反应， 公式的药代动力学和安全性。拟议的研究将为FDA IND奠定基础 应用和临床翻译，并将建立Fasudil-Plus-DN的Car脂质体作为一种新颖的 适用于PAH患者的可吸收治疗选择：a）专门针对高血压的肺部 脉管系统和b）通过Rho A/Rho激酶和没有供体提供协同理论的好处 途径，没有全身性血管舒张的不利副作用。我们的方法是创新的， 因为我们将确定针对PAH的有针对性的两次药物吸入疗法的慢性效率。我们有一个 强大的商业化计划制定了我们的汽车改装公式，将受到汽车专利的保护 肽，我们有一个研究人员的团队积累了临床医生，统计学家，肽化学家，肺 生物学家，行业退伍军人和制药科学家。重要的是，我们建议解决一个未满足的 通过开发有效的药物治疗来治疗不足和毁灭性疾病，医疗需求。