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: 9907530
• 负责人: Fakhrul Ahsan
• 金额: $ 33万
• 依托单位: VASCULAR BIOSCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907530
• 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) 影响每百万人约 15-50 人，每年夺走 ≥20,000 人的生命 在美国。它影响每个民族、种族、年龄和性别，并摧毁高危患者 患有艾滋病毒、系统性硬化症和镰状细胞病。这种疾病影响的女性多于男性；成人 PAH 患者在诊断后的生存时间不会超过五年。 PAH 甚至影响新生儿和 幼儿：如果不及时治疗，患有多环芳烃的儿童将无法活过两岁生日。目前服用的药物 无法降低死亡率、延长生存时间或提高患者的生活质量。许多患者没有反应 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，或接受肺移植。与“疾病皇帝”（癌症和中风）不同， PAH 尚未受到药物发现机构的太多关注，因此进展 这种“孤儿”疾病的药物开发和长期管理非常有限。由于多环芳烃 只影响相对少数的患者，制药商并未将其作为优先事项 找到治疗 PAH 的方法，这种疾病首次在 20 世纪 50 年代被描述。在这个项目中，我们建议开发一个 由法舒地尔（一种 rho 激酶抑制剂）和 DETA NONOate (DN)（一种一氧化氮）组成的可靶向吸入制剂 （否）捐赠者。我们将通过将法舒地尔和 DN 这两种药物封装在药物中来开发这种联合疗法。 用环肽 CAR (CARSKNKDC) 修饰的脂质体，优先在 高血压肺动脉。在一系列的研究中，我们证明了CAR修饰的脂质体 含有法舒地尔和 DN 的药物可降低平均肺动脉压 (mPAP)，从而改善各种症状 肺动脉重构的特点。在此快速通道申请中，我们将评估 我们基于脂质体制剂的靶向组合的临床转化和商业开发 PAH 的治疗。在第一阶段，我们将研究长期施用吸入式CAR-的效果。 法舒地尔加 DN 的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，并确定检测纳克水平的测定的灵敏度和特异性 血浆中的法舒地尔和NO。在第二阶段，我们将进行研究以确定剂量反应， 制剂的药代动力学和安全性。拟议的研究将为 FDA IND 奠定基础 应用和临床转化，并将将法舒地尔加DN的CAR脂质体确立为一种新型的、 PAH 患者的吸入式治疗选择将： a) 专门针对肺动脉高压 b) 通过 Rho A/Rho 激酶和 NO 供体提供协同治疗益处 途径，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， 因为我们将确定针对 PAH 的靶向两种药物吸入疗法的长期疗效。我们有一个 稳健的商业化计划已到位，我们的 CAR 改良配方将受到 CAR 专利的保护 我们有一个由临床医生、统计学家、肽化学家、肺科医师组成的研究团队 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满足的问题 通过开发有效的药物疗法来治疗尚未充分研究的毁灭性疾病，从而满足医疗需求。