Thrombopoietin Targeting in Myeloproliferative Neoplasms

项目摘要/摘要 骨髓增生性肿瘤(MPN)患者的治疗仅限于姑息和 减轻增殖性血细胞计数及其影响的细胞还原剂。小分子 选择性酪氨酸激酶(JAK1/JAK2)抑制剂也被证明提供了适度的患者益处， 包括减少症状和提高生活质量。尽管有可用的治疗方法， 晚期MPN患者的存活率仍然很低，一些患者不可避免地成为 对所有可用的疗法都是无效的。因此，对新药的医学需求尚未得到满足。 这可以安全地缓解MPN症状，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 Aronora的专利候选药物AB062，一种血小板生成素偶联反义寡核苷酸 (THPO-ASO)，单独使用或与其他药物联合使用，作为一种治疗慢性疾病的新疗法 骨髓增生性疾病。THPO-ASO对小鼠肝组织血小板生成素基因转录的抑制作用 小鼠和灵长类动物模型均可降低血清促血小板生成素(TPO)水平，并导致剂量- 依赖TPO浓度的下游细胞效应的依赖性减少。我们的合作伙伴- 研究人员和其他人已经表明，TPO的缺乏主要导致某些特定的 TPO依赖的突变JAK2携带MPN干细胞，同时保留健康的骨髓前体细胞。 靶向THPO/MPL/JAK2轴也可以减轻小鼠MPN模型中的MPN表型，包括 增殖性血细胞减少和脾肿大。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。我们第一阶段的目标 SBIR快速通道项目的目的是确认单独使用小鼠THPO-ASO治疗[或在 与JAK2抑制剂Ruxolitinib联合使用可以改善转基因患者的疾病结局 小鼠MPN模型。在达到这个里程碑后，我们会把这些研究扩展至第二阶段：1) 在小鼠MPN移植模型中评估小鼠THPO-ASO，将使我们能够评估 THPO-ASO对恶性克隆负荷的影响2)评价THPO-ASO的可逆性 并评估与JAK抑制剂ruxolitnib的协同作用，以及3)筛选和制造AB062，a 靶向人类THPO的候选药物ASO。积极的结果将证明进一步的商业 开发，并将帮助支持用于评估AB062的研究性新药申请 迫切需要新的和创新的晚期骨髓增殖性疾病患者 治疗。

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.