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）影响每百万人中约15-50人，每年夺去≥ 20，000人的生命 在美国它影响到每一个民族、种族、年龄和性别，并对高危患者进行筛查。 患有艾滋病系统性硬化症和镰状细胞病这种疾病对女性的影响比男性多;成年人 PAH患者在诊断后的寿命不超过5年。PAH甚至影响新生儿， 幼儿：如果不进行治疗，患有PAH的儿童无法活过2岁生日。当前药物 不能降低死亡率、延长生存时间或提高患者生活质量。许多患者对 现有的口服和吸入抗PAH药物;因此，他们必须接受持续静脉输注， 前列环素类似物，或进行肺移植。与“疾病之王”（癌症和中风）不同， PAH尚未受到药物发现机构的关注，因此， 这种“孤儿”疾病的药物开发和长期管理一直很少。由于PAH 只影响相对较少的患者，制药商没有优先考虑 寻找治疗多环芳烃的方法，这种疾病于20世纪50年代首次被描述。在这个项目中，我们建议开发一个 一种rho激酶抑制剂法舒地尔和一种一氧化氮DETA NONOate（DN）靶向和可吸入制剂 (NO)供体我们将通过将法舒地尔和DN两种药物封装在 脂质体修饰的环肽，CAR（CARSKNKDC），它优先积累在 肺动脉高压在一系列研究中，我们已经证明CAR修饰的脂质体 含法舒地尔和DN降低了平均肺动脉压（mPAP），这改善了各种 肺动脉重构的特征。在此快速通道应用程序中，我们将评估 我们的靶向脂质体制剂组合的临床转化和商业开发 治疗PAH。在第一阶段，我们将研究长期吸入CAR的效果， 法舒地尔加DN脂质体制剂对肺血流动力学、肺重塑和右心室的影响 (RV)肥大，并确定用于检测纳克水平的 血浆法舒地尔和NO。在第二阶段，我们将进行研究，以确定剂量反应， 药物代谢动力学和制剂的安全性。拟议的研究将为FDA IND奠定基础 应用和临床转化，并将建立法舒地尔加DN的CAR-脂质体作为一种新的， PAH患者的可吸入治疗选择：a）特异性靶向高血压肺动脉高压 和B）通过Rho A/Rho激酶和NO供体两者提供协同治疗益处 通路，而没有全身血管舒张的附加不良副作用。我们的方法是创新的， 因为我们将确定PAH靶向双药吸入疗法的长期疗效。我们有一个 我们的CAR改良制剂将受到CAR专利的保护， 肽，我们有一个由临床医生组成的研究团队，统计学家，肽化学家，肺 生物学家、行业资深人士和制药科学家。重要的是，我们建议解决一个未得到满足的 通过开发一种有效的药物疗法来治疗一种调查不足的毁灭性疾病，满足医疗需求。