Nitazoxanide as a Novel Therapy for Rare Disease Lymphangioleiomyomatosis and Tuberous Sclerosis

硝唑尼特作为罕见疾病淋巴管平滑肌瘤病和结节性硬化症的新疗法

基本信息

批准号：
10258194
负责人：
VERA P KRYMSKAYA
金额：
$ 25.64万
依托单位：
BIOSPUTNIK LLC
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：
2021-04-10 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10258194
关键词：
1 year old Address Adverse effects Affect Age Animals Antibodies Antiparasitic Agents Antiprotozoal Agents Apoptosis Authorization documentation Benign Binding Brain Businesses Categories Cell Culture Techniques Cell Line Cell Proliferation Cell Survival Cell model Cells Cessation of life Clinical Complex Cryptosporidium parvum Cyst Development Diarrhea Disadvantaged Disease Dose Enhancers Evaluation Eye FDA approved FRAP1 gene Female of child bearing age Fibroblasts Future Genetic Genetic Diseases Giardia lamblia Goals Grant Growth Heart Hematoxylin and Eosin Staining Method Human Human Cell Line Immunodeficient Mouse Immunosuppressive Agents In Vitro Incentives Individual Inherited Injections Investigation Kidney Laboratories Legal patent Lesion Life Lung Lung Neoplasms Lung Transplantation Lung diseases Lymphangiogenesis Lymphangioleiomyomatosis Lymphatic Obstruction Mass Spectrum Analysis Medical Modeling Molecular Target Morphology Mus Mutation NQO1 gene Neoplasms Nodule Nude Mice Null Lymphocytes Organ Orphan Drugs Oxidoreductase Pathologic Pathway interactions Patients Pennsylvania Pregnancy Prevention Property Quinones Rare Diseases Recurrence Research Resort SLC12A3 gene Safety Serious Adverse Event Shortness of Breath Signal Pathway Signal Transduction Sirolimus Skin Smooth Muscle Myocytes Stains Structure Structure of parenchyma of lung TSC1 gene TSC2 gene Technology Therapeutic Tissues Titrations Toxic effect Translating Treatment Efficacy Tuberous Sclerosis Tuberous sclerosis protein complex Tumor Suppressor Genes United States Universities Vascular Endothelial Growth Factor D Western Blotting Woman base cell immortalization child bearing clinical development commercial application commercialization direct application experimental study gene function improved in vivo inhibitor/antagonist mTOR Inhibitor mouse model neoplastic nitazoxanide novel novel therapeutics prevent standard of care therapy development treatment comparison treatment effect tuberous sclerosis patients tumor

项目摘要

ABSTRACT Tuberous sclerosis (TS), also called tuberous sclerosis complex, is a rare, multi-systemic genetic and often life- threatening disease that causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. Lymphangioleiomyomatosis (LAM) is a TS-related tumor-like disorder. Both occur as a consequence of an inherited or sporadic mutation in either the TSC1 or TSC2 gene, which function as negative regulators of the mTOR pathway. Uncontrolled mTORC1 activity leads to the neoplastic proliferation of abnormal smooth muscle cells (LAM cells) in the lungs, progressive shortness of breath, recurrent pneumothoraxes, and loss of pulmonary tissue structure and function. TS affects as many as 25,000 to 40,000 individuals in the United States and about 1 to 2 million individuals worldwide. LAM is a rare disease affecting women in childbearing age. The first and only FDA-approved treatment for LAM is the immunosuppressant sirolimus (Rapamune©), marketed since 2015 by Pfizer. It is the current standard-of-care and acts by inhibiting mTORC1. Sirolimus has several clinical disadvantages, including a considerable number of non-responders, severe adverse events due to its immunosuppressive properties and pregnancy category C, limiting its use in women of childbearing age. Thus, there is a high unmet medical need to develop alternative and safer treatment options for LAM and TS. We have identified Nitazoxanide (hereafter NTZ; Alinia©), an antiprotozoal FDA-approved and safe therapy for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum in patients 1 year of age or older, as a potential novel therapy for LAM/TS. Using Capture Compound Mass Spectrometry technology, we discovered NAD(P)H quinone oxidoreductase (NQO1) as the human target of Nitazoxanide. Furthermore, we have shown that NTZ is effective in inhibiting mTORC1 related cellular signaling in three different LAM related murine and human cell lines addressing the underlying pathological mechanism of LAM/TS. Our goal for this grant is the investigation of NTZ’s efficacy for the treatment of LAM/TS. Aim 1 will be the in vivo proof of concept comparing three dose levels of NTZ in a TSC2-null murine model developed at the laboratory of Prof. Krymskaya at the University of Pennsylvania. It will evaluate prevention of TSC2-null lesion growth, immunohistochemical and lung morphology changes and animal survival in a murine LAM model. Aim 2 will cover an in vitro study, investigating underlying cellular effects on mTOR and related signaling pathways. The in vitro study will investigate NTZ's effects in LAM-derived AML (LAMD) cells and immortalized TSC2-null cell cultures of human origin followed by more detailed mTORC1 interactions studies. In addition to the monotherapeutic NTZ approach, dose reduction potential for dose-toxicity prone rapamycine with NTZ add-on will be explored. This project aims to develop a novel therapy for patients with the devastating diseases of LAM/TS. Based on NTZ's excellent safety profile as an approved antiprotozoal drug, positive efficacy results in our studies would enable an accelerated clinical development under FDA section 505 (2)(b) approval pathway and orphan disease designation.

抽象的结节性硬化症（TS），也称为结节性硬化症复合物，是一种罕见的，多系统的遗传，通常是生命的威胁性疾病会导致良性肿瘤在大脑和其他重要器官（例如Kidsneys）中生长心，眼睛，肺和皮肤。淋巴管肌瘤病（LAM）是一种与TS相关的肿瘤样疾病。两者都是作为一个 TSC1或TSC2基因中遗传或零星突变的结果，其作用为负 MTOR路径的调节器。不受控制的MTORC1活性导致异常的肿瘤增殖肺中的平滑肌细胞（LAM细胞），呼吸的渐进短暂，复发性气胸和丧失肺组织结构和功能。 TS在美国影响多达25,000至40,000个人全球约1至200万个人。林是一种罕见的疾病，影响育龄年龄的妇女。第一个和 LAM的只有FDA批准的治疗方法是免疫抑制剂西洛里木斯（Rapamune©），自2015年以来销售辉瑞。它是当前的护理标准，并通过抑制MTORC1来起作用。西罗莫司（Sirolimus）有几次临床灾难，包括考虑数量的非反应数，由于其免疫抑制特性而导致的严重不良事件和妊娠C类C，限制其在育龄妇女中的使用。那是一个很高的未满足医疗的需求为LAM和TS开发替代和安全的治疗选择。我们已经确定了Nitazoxanide（以下称NTZ; Alinia©），这是一种抗菌FDA批准和安全的治疗 1岁或以上的患者，由贾第鞭毛虫或隐孢子虫parvum引起的腹泻的治疗 LAM/TS的潜在新型疗法。使用捕获复合质谱技术，我们发现了 NAD（P）H喹酮氧化激酶（NQO1）作为硝酸氧化物的人类靶标。此外，我们已经表明 NTZ有效抑制三种不同LAM相关的鼠和人类细胞中MTORC1相关的细胞信号传导解决LAM/TS的潜在病理机制的线。这项赠款的目标是NTZ对LAM/TS治疗的效率的投资。 AIM 1将是体内证明概念比较了在教授实验室开发的TSC2-null鼠模型中的三个剂量水平的NTZ。宾夕法尼亚大学的Krymskaya。它将评估预防TSC2-NULL病变生长，在鼠类LAM模型中，免疫组织化学和肺形态变化和动物存活。 AIM 2将涵盖一项体外研究，研究对MTOR和相关信号通路的潜在细胞影响。体外研究将研究NTZ在LAM衍生的AML（LAMD）细胞中的作用和永生的TSC2-NULL细胞人类来源的培养，然后进行更详细的MTORC1相互作用研究。除了单层 NTZ方法，将探索易于使用NTZ附加组件的剂量毒性的剂量毒性潜力。该项目旨在为LAM/TS毁灭性疾病的患者开发一种新的疗法。基于NTZ的出色的安全性概况作为批准的抗植物药物，在我们的研究中，阳性效率将使我们能够根据FDA第505（2）（b）批准途径和孤儿疾病设计的加速临床发展。