Thrombopoietin Targeting in Myeloproliferative Neoplasms

骨髓增殖性肿瘤中的血小板生成素靶向

基本信息

批准号：
10484073
负责人：
Christina U Lorentz
金额：
$ 30.18万
依托单位：
ARONORA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-22 至 2023-04-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10484073
关键词：
ABL1 gene Address Adverse effects Alleles Antisense Oligonucleotides Biological Blood Blood coagulation Bone Marrow Bone Marrow Stem Cell Caring Chronic Chronic Myeloproliferative Disorder Clinical Clinical Research Clinical Trials Code Data Development Disease Disease Outcome Disease Progression Dose Engineering Extrahepatic Extramedullary Hematopoiesis Funding Gene Expression Genetic Genetic Transcription Hematological Disease Hematopoietic Hematopoietic stem cells Hemorrhage Hepatic Histologic Histology Human Hypercellular Bone Marrow In Vitro Innovative Therapy Investigational Drugs Investigational New Drug Application JAK1 gene JAK2 gene Janus kinase Lead Legal patent Letters Leukocytosis Libraries Liver MPL gene Malignant - descriptor Medical Messenger RNA Modeling Morbidity - disease rate Mus Mutation Myelofibrosis Myeloproliferation Myeloproliferative disease Neoplasms Papio Patients Pharmaceutical Preparations Pharmacologic Substance Pharmacological Treatment Pharmacology Phase Phase II Clinical Trials Phenotype Platelet Count measurement Preparation Primates Process Protein Tyrosine Kinase Publishing Quality of life Refractory Research Research Personnel Safety Serum Signal Transduction Site Small Business Innovation Research Grant Splenomegaly Symptoms THPO gene Therapeutic Therapeutic Agents Thrombocytopenia Thrombopoietin Toxic effect Transgenic Organisms Treatment Efficacy Work deprivation drug candidate effective therapy efficacy evaluation exhaustion improved in silico in vivo industry partner inhibitor mimetics mortality mouse model mutant neoplasm therapy novel novel therapeutics palliative patient population preclinical development preclinical toxicity prevent product development progenitor prospective reduce symptoms screening small molecule stem cell expansion stem cells symptomatology synergism thrombocytosis transplant model

项目摘要

Project Summary/Abstract Treatment of patients with myeloproliferative neoplasms (MPNs) is limited to palliative and cytoreductive agents that mitigate proliferative blood counts and their effects. Small molecule selective tyrosine kinase (JAK1/JAK2) inhibitors were also shown to provide modest patient benefit, including reduced symptomatology and improved quality of life. Despite the available therapies, survival remains poor in patients with advanced forms of MPN, and some patients inevitably become refractory to all available therapies. Consequently, there is an unmet medical need for a new drug that can safely mitigate MPN symptoms and, ideally, also alter the long-term course of the disease. To address this important need, we propose to develop and investigate the therapeutic potential of Aronora’s proprietary drug candidate AB062, a thrombopoietin conjugate antisense oligonucleotide (THPO-ASO), to be used alone or in addition to other drugs, as a novel therapeutic for chronic myeloproliferative disorders. Our THPO-ASO inhibits hepatic thrombopoietin gene transcription in both murine and primate models, reduces serum thrombopoietin (TPO) levels, and results in dose- dependent reduction of TPO concentration-dependent downstream cellular effects. Work by our co- investigators and others has shown that TPO deprivation predominantly results in depletion of certain TPO-dependent mutant JAK2 carrier MPN stem cells while sparing healthy bone marrow progenitors. Targeting THPO/MPL/JAK2 axis also mitigates the MPN phenotype in murine MPN models, including reduction in proliferative blood counts and splenomegaly. These observations support our hypothesis that THPO-ASO could favorably alter the natural trajectory of certain MPNs. Our objective for Phase I of this SBIR Fast-Track project is to confirm that murine THPO-ASO treatment alone [or in combination with the JAK2 inhibitor, ruxolitinib,] can improve disease outcomes in a transgenic murine MPN model. Upon reaching this milestone, we will extend these studies into Phase II by: 1) evaluating murine THPO-ASO in a murine MPN transplant model that will allow us to assess the effects of THPO-ASO on the malignant clonal burden, 2) evaluating the reversibility of THPO-ASO and assess for synergy with the JAK inhibitor ruxolitnib, and 3) screen for and manufacture AB062, a drug-candidate ASO that targets human THPO. Positive results will justify further commercial development, and will help support an Investigational New Drug application for evaluating AB062 in patients with advanced myeloproliferative disorders who are in desperate need of new and innovative therapies.

项目概要/摘要骨髓增生性肿瘤 (MPN) 患者的治疗仅限于姑息治疗和减轻血细胞计数增殖及其影响的细胞减灭剂。选择性酪氨酸激酶 (JAK1/JAK2) 抑制剂也被证明可以为患者带来一定的益处，尽管有可用的治疗方法，但仍可减少症状并提高生活质量，晚期 MPN 患者的生存率仍然很差，一些患者不可避免地会变得所有可用疗法均无效，因此对新药的医疗需求尚未得到满足。可以安全地减轻 MPN 症状，并且理想情况下还可以改变疾病的长期病程。为了满足这一重要需求，我们建议开发和研究治疗潜力 Aronora 的专有候选药物 AB062，一种血小板生成素缀合物反义寡核苷酸（THPO-ASO），单独使用或与其他药物联合使用，作为慢性病的新型治疗方法我们的 THPO-ASO 抑制肝血小板生成素基因转录。在小鼠和灵长类动物模型中，血清降低了血小板生成素（TPO）水平，并导致剂量- TPO 浓度依赖性下游细胞效应的依赖性减少研究人员和其他人已经表明，TPO 剥夺主要导致某些物质的消耗 TPO 依赖性突变型 JAK2 携带 MPN 干细胞，同时保留健康的骨髓祖细胞。靶向 THPO/MPL/JAK2 轴还可减轻小鼠 MPN 模型中的 MPN 表型，包括增殖性血细胞计数减少和脾肿大这些观察结果支持我们的假设。 THPO-ASO 可以有利地改变某些 MPN 的自然轨迹。该 SBIR 快速通道项目的目的是确认小鼠 THPO-ASO 单独治疗 [或在与 JAK2 抑制剂 ruxolitinib 组合，]可以改善转基因药物的疾病结果鼠 MPN 模型达到这一里程碑后，我们将通过以下方式将这些研究扩展到 II 期：1) 在小鼠 MPN 移植模型中评估小鼠 THPO-ASO，这将使我们能够评估 THPO-ASO 对恶性克隆负荷的影响，2) 评估 THPO-ASO 的可逆性并评估与 JAK 抑制剂 ruxolitnib 的协同作用，以及 3) 筛选和生产 AB062（一种靶向人类 THPO 的候选药物 ASO 的积极结果将证明进一步商业化是合理的。开发，并将帮助支持研究性新药申请，以评估 AB062 急需新药和创新药物的晚期骨髓增生性疾病患者疗法。