Thrombopoietin Targeting in Myeloproliferative Neoplasms

骨髓增殖性肿瘤中的血小板生成素靶向

• 批准号: 10731078
• 负责人: Christina U Lorentz
• 金额: $ 70.03万
• 依托单位: ARONORA, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-22 至 2025-06-26
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731078
• 关键词: Thrombopoietin; Targeting; Myeloproliferative; Neoplasms; Thrombopoietin; Targeting; Myeloproliferative; Neoplasms

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.

项目摘要/摘要 骨髓增生性肿瘤（MPN）患者的治疗仅限于姑息治疗 减轻增生剂血液计数及其作用的细胞还原剂。小分子 选择性酪氨酸激酶（JAK1/JAK2）抑制剂也被证明可提供适度的患者益处， 包括症状减少和改善生活质量。尽管有可用的疗法， 在MPN晚期形式的患者中，生存仍然很差，有些患者不可避免地会成为 对所有可用疗法的难治性。因此，对新药的医疗需求未满足 这可以安全地减轻MPN症状，理想情况下也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 Aronora的专有药物候选AB062，一种血小板蛋白偶联的反义寡核苷酸 （thpo-aso），单独使用或除其他药物以外用作慢性的新疗法 骨髓增生性疾病。我们的THPO-ASO抑制肝血小板素基因转录 鼠和灵长类动物模型都降低了血小板素（TPO）水平，并导致剂量 - TPO浓度依赖性下游细胞效应的依赖性降低。我们的共同工作 研究人员和其他人表明，TPO剥夺主要导致某些 依赖TPO的突变体JAK2载体MPN干细胞，同时保留健康的骨髓祖细胞。 靶向THPO/MPL/JAK2轴也可以减轻鼠MPN模型中的MPN表型，包括 减少血液计数和脾肿大的降低。这些观察结果支持我们的假设 THPO-ASO最好改变某些MPN的自然轨迹。我们对第一阶段的目标 这个SBIR快速轨道项目是为了确认单独使用Murine thpo-aso治疗[或 与JAK2抑制剂ruxolitinib结合]可以改善转基因的疾病预后 鼠MPN模型。达到这一里程碑后，我们将这些研究扩展到II阶段：1） 评估鼠MPN移植模型中的鼠THPO-ASO，该模型将使我们能够评估 THPO-ASO对恶性克隆伯嫩的影响，2）评估THPO-ASO的可逆性 并评估与JAK抑制剂Ruxolitnib的协同作用，3）筛选和制造AB062，A 靶向人类THPO的药物candation ASO。积极的结果将证明进一步的广告合理 开发，并将有助于支持调查新药应用，以评估AB062 急需新创新的晚期骨髓增生性疾病的患者 疗法。