Developing novel therapeutics for the treatment of mastocytosis

开发治疗肥大细胞增多症的新疗法

• 批准号: 10742448
• 负责人: Jianya Peng
• 金额: $ 5.5万
• 依托单位: NEMAGEN DISCOVERIES, INC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2023-04-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10742448
• 关键词: Abdominal Pain; Acceleration; Address; Anaphylaxis; Capital; Carbon Dioxide; Carbonic Anhydrase Inhibitors; Cellular biology; Complement; Development; Disease; Doctor of Philosophy; Enzyme Inhibitor Drugs; Enzymes; Face; Family; Foundations; Funding; Grant; Health; Homeostasis; Human; Industry; Innovation Corps; Lead; Life; Mediating; Medicine; Metabolic; Mission; Mus; Names; New Jersey; Organ; Patients; Peer Review; Phase; Prognosis; Publishing; Research; Role; Small Business Innovation Research Grant; Technology; Time; Tissues; Urticaria; arm; carbonate dehydratase; design; disabling symptom; drug discovery; inhibitor; mast cell; mastocytosis; member; mouse model; new therapeutic target; novel; novel therapeutics; pharmacologic; prevent; programs; reduce symptoms; response; stem cells

Executive Summary of Predicate SBIR Phase I Grant and Team The overall objective of our predicate SBIR Phase I grant, which started in June 2022, is to develop novel and potent compounds for treating mastocytosis. Mastocytosis is a rare set of diseases, characterized by the increased presence of mast cells in various tissues and organs. Patients suffering from mastocytosis often have diverse triggers that promote the activation of mast cells and subsequently the onset of debilitating symptoms, ranging from hives and abdominal pain to organ damage and life-threatening anaphylaxis. Although treatment options for mastocytosis patients exist, they are non-specific and are often limited to symptom alleviation and fail to adequately address the incapacitating and life-threatening prognoses mastocytosis patients face. Therefore, better therapies are urgently needed and NemaGen’s mission is to address this substantial need. Our cutting-edge technologies have, for the first time, identified a unique mast cell progenitor that is defined by its expression of the enzyme Carbonic anhydrase 1 (Car1). Carbonic anhydrases are a family of metabolic enzymes, known for their important roles in regulating pH and CO2 homeostasis. However, their role in mast cell development was unappreciated. NemaGen’s peer-reviewed and published findings have demonstrated that pharmacologically or genetically targeting Car1 is sufficient to prevent murine and human mast cell development. Moreover, we have shown that Car1 inhibition is sufficient to prevent mast cell responses in murine models of mastocytosis. Collectively, our exciting findings suggest that Car1 represents a new therapeutic target to treat mastocytosis and other mast cell-mediated diseases. We have developed a highly efficient drug discovery program, which is being accelerated with the assistance of our SBIR Phase I grant funding and funding from the venture capital arm of the New Jersey Health Foundation (NJHF). Since receiving our Phase I SBIR funding, we have engaged a leading medicinal chemist consultant to complement NemaGen’s established expertise in carbonic anhydrase enzymes and mast cell biology. This has resulted in the development of multiple lead compounds with more than 100-fold higher potency than established Car1 inhibitors (Table. 1) helping us to further advance our Phase 1 Aims. Overall, the specific aims of the proposed Phase I research were to: (1) Design, synthesize and optimize novel carbonic anhydrase inhibitors. (2) Evaluate the effects of Car enzyme inhibitors on enzymatic function and mast cell development. Our proposed I-Corps team will include the following three members. Member Names Role Nick Shubin, PhD NemaGen CEO Scott Alpizar, PhD Industry Expert, Venture Capitalist Jianya Peng, PhD PD/PI All three members are highly motivated and committed to the time requirements of the program.

同品种器械SBIR第一阶段赠款和团队的执行摘要 我们于2022年6月开始的同品种SBIR第一阶段资助的总体目标是开发新型 和用于治疗肥大细胞增多症的有效化合物。肥大细胞增多症是一种罕见的疾病，其特征是 各种组织和器官中肥大细胞的增加。肥大细胞增多症患者 通常有不同的触发因素，促进肥大细胞的激活，随后发生 使人衰弱的症状，从荨麻疹和腹痛到器官损伤和危及生命 过敏反应虽然存在肥大细胞增多症患者的治疗选择，但它们是非特异性的， 通常仅限于缓解症状，未能充分解决丧失能力和危及生命的问题 肥大细胞增多症患者面部肿胀。因此，迫切需要更好的治疗方法， 使命就是满足这一巨大需求。 我们的尖端技术首次发现了一种独特的肥大细胞祖细胞， 通过其碳酸酐酶1（Car 1）的表达来定义。碳酸酐酶是一个家族， 代谢酶，以其在调节pH和CO2稳态中的重要作用而闻名。但他们的 在肥大细胞发育中的作用未被认识到。NemaGen的同行评审和发表的研究结果 证明了以Car 1为靶点的基因治疗或基因治疗足以预防鼠和 人肥大细胞发育。此外，我们已经表明，Car 1抑制足以防止肥大细胞增多， 肥大细胞增多症小鼠模型中的细胞反应。总的来说，我们令人兴奋的发现表明， 代表了治疗肥大细胞增多症和其它肥大细胞介导的疾病的新的治疗靶点。 我们研制出一种高效的药物 正在加速的发现计划 在我们SBIR第一阶段赠款的帮助下， 资金和风险投资部门的资金 新泽西健康基金会（NJHF）。 自从收到第一阶段SBIR资金以来，我们 聘请了一位顶尖的药物化学顾问 以补充NemaGen现有的专业知识 碳酸酐酶和肥大细胞生物学。这导致了多种先导化合物的开发， 比现有的Car 1抑制剂更有效（表。1)帮助我们进一步推进我们的第一阶段目标。 总体而言，拟议的第一阶段研究的具体目标是： (1)新型碳酸酐酶抑制剂的设计、合成与优化。 (2)评价Car酶抑制剂对酶功能和肥大细胞发育的影响。 我们提议的I军团小组将包括以下三名成员。 成员名称角色 NemaGen首席执行官Nick Shubin博士 Scott Alpizar，博士 行业专家，Venture 资本主义 Jianya Peng，PhD PD/PI 所有三名成员都非常积极，并致力于该计划的时间要求。