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: 10478270
• 负责人: Fakhrul Ahsan
• 金额: $ 100.69万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478270
• 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; Homing; 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 arterial remodeling; Pulmonary artery structure; Quality of life; Race; Rare Diseases; Rattus; Records; Research Personnel; Rho-associated kinase; Right Ventricular Hypertrophy; 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; Vasodilation; Vasodilator Agents; Veterans; Woman; acute toxicity; analog; base; clinical translation; commercialization; common treatment; drug discovery; drug inhalation; experimental study; exposure route; fasudil; genotoxicity; heart function; hemodynamics; high risk; hypertensive; improved; inhibitor; innovation; kinase inhibitor; liver injury; men; mortality; nanocarrier; novel; phosphodiesterase V; pre-clinical; prevent; pulmonary arterial hypertension; pulmonary arterial pressure; pulmonary vascular remodeling; response; rho; right ventricular failure; 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.

每百万人中约有15-50人患有肺动脉高压，每年有20,000人死于≥ 在美国。它影响到每个民族、种族、年龄和性别，并摧毁了高危患者 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比男性更多；成人 PAH患者在确诊后的寿命不超过五年。多环芳烃甚至会影响新生儿和 蹒跚学步的孩子：如果不治疗，患有PAH的儿童无法活过他们的两岁生日。目前的药物 未能降低死亡率、延长生存时间或提高患者的生活质量。许多患者对此无反应 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“疾病之王”(癌症和中风)不同， PAH还没有得到药物发现机构的太多关注，所以 这种“孤儿”疾病的药物开发和长期治疗微乎其微。由于PAH 只影响相对较小数量的患者，制药商并未将其作为优先事项 找到治疗PAH的方法，这是一种在20世纪50年代首次被描述的疾病。在这个项目中，我们建议开发一种 Rho-Kinase抑制剂法舒地尔和一氧化氮DETA NONOate(DN)的靶向和可吸入制剂 (否)捐赠人。我们将开发这种联合疗法，通过将法舒地尔和糖尿病肾病这两种药物封装在一起 用环肽CAR(CARSKNKDC)修饰的脂质体在体内优先累积 高血压的肺动脉。在一系列研究中，我们已经证明了汽车修饰的脂质体 含法舒地尔和糖尿病肾病可降低平均肺动脉压(MPAP)，从而改善各种 肺动脉重塑的特点。在此Fast-Track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翻译和商业开发 帕金森病的治疗。在第一阶段，我们会研究长期吸入车辆的效果- 法舒地尔+糖尿病肾病脂质体制剂对肺血流动力学、肺重塑和右心的影响 (RV)肥大，并确定检测纳克水平的敏感性和特异性 法舒地尔和NO在血浆中。在第二阶段，我们将进行研究，以确定剂量反应， 这些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 应用和临床翻译，并将建立法舒地尔+DN的CAR脂质体作为一种新的和 针对PAH患者的吸入性治疗选择：a)专门针对高血压的肺 血管系统，以及b)通过Rho A/Rho激酶和NO供体提供协同治疗益处 途径，没有全身血管扩张的附加副作用。我们的方法是创新的， 因为我们将确定有针对性的两种药物吸入疗法治疗PAH的慢性疗效。我们有一个 强大的商业化计划到位，我们的汽车改装配方将受到汽车专利的保护 多肽，我们有一个由临床医生、统计学家、多肽化学家、肺部 生物学家、行业老手和一位制药科学家。重要的是，我们建议解决一个未满足的问题 通过开发一种有效的药物疗法来治疗一种未得到充分研究和毁灭性的疾病，从而满足医疗需求。

项目成果

Multicellular Cell Seeding on a Chip: New Design and Optimization towards Commercialization.

• DOI: 10.3390/bios12080587
• 发表时间: 2022-08-01
• 期刊: Biosensors

Intratracheally Administered Peptide-Modified Lipid Admixture Containing Fasudil and/or DETA NONOate Ameliorates Various Pathologies of Pulmonary Arterial Hypertension.

• DOI: 10.3390/ph16121656
• 发表时间: 2023-11-28
• 期刊: Pharmaceuticals (Basel, Switzerland)
• 作者: Sarkar T;Moinuddin SM;Isbatan A;Chen J;Mann D;Ahsan F
• 通讯作者: Ahsan F

An Overview of Organ-on-a-Chip Models for Recapitulating Human Pulmonary Vascular Diseases.

用于重现人类肺血管疾病的器官芯片模型概述。

• DOI: 10.1007/978-3-031-26625-6_13
• 发表时间: 2023
• 期刊: Advances in experimental medicine and biology
• 作者: Nguyen,Trieu;Ahsan,Fakhrul
• 通讯作者: Ahsan,Fakhrul

Multilayer Soft Photolithography Fabrication of Microfluidic Devices Using a Custom-Built Wafer-Scale PDMS Slab Aligner and Cost-Efficient Equipment.

• DOI: 10.3390/mi13081357
• 发表时间: 2022-08-20
• 期刊: MICROMACHINES
• 影响因子: 3.4
• 作者: Nguyen, Trieu;Sarkar, Tanoy;Tran, Tuan;Moinuddin, Sakib M.;Saha, Dipongkor;Ahsan, Fakhrul
• 通讯作者: Ahsan, Fakhrul

An evolving perspective on novel modified release drug delivery systems for inhalational therapy.

• DOI: 10.1080/17425247.2023.2175814
• 发表时间: 2023-03
• 期刊: EXPERT OPINION ON DRUG DELIVERY
• 影响因子: 6.6
• 作者: Hye, Tanvirul;Moinuddin, Sakib M. M.;Sarkar, Tanoy;Nguyen, Trieu;Saha, Dipongkor;Ahsan, Fakhrul
• 通讯作者: Ahsan, Fakhrul