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

基本信息

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
项目类别：
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

项目摘要

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，它影响着每个民族、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的女性多于男性； PAH 患者在诊断后存活时间不会超过五年，甚至会影响新生儿。幼儿：如果不接受当前的药物治疗，受多环芳烃影响的儿童将无法活过两岁生日。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，因此在这方面取得的进展自 PAH 以来，这种“孤儿”疾病的药物开发和长期治疗一直很少。只影响相对少数的患者，药品制造商尚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，我们建议开发一种方法。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 (NO) 供体。我们将通过将法舒地尔和 DN 封装在其中来开发这种联合疗法。用环肽 CAR (CARSKNKDC) 修饰的脂质体，优先在在一系列研究中，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)，从而改善各种症状在此快速通道应用中，我们将评估肺动脉重塑的潜力。我们基于脂质体制剂的靶向组合的临床转化和商业开发在第一阶段，我们将研究长期吸入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检测的灵敏度和特异性在第二阶段，我们将进行研究以确定剂量反应，拟议的研究将为 FDA IND 奠定基础。应用和临床转化，并将法舒地尔加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我们的方法是创新的，没有系统性血管舒张的附加不良副作用。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。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殖民者、统计学家、肽化学家、肺脏研究人员组成的研究团队重要的是，我们建议解决未满足的问题。通过有效的药物治疗来治疗尚未充分研究的毁灭性疾病而产生的医疗需求。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
作者：
通讯作者：

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)
影响因子：
0
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
影响因子：
0
作者：
Nguyen,Trieu;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

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