Converting gut endocrine cells to glucose-responsive insulin-producing cells by selective FOXO1 inhibition to cure insulin-dependent diabetes

通过选择性抑制 FOXO1 将肠道内分泌细胞转化为葡萄糖反应性胰岛素生成细胞以治疗胰岛素依赖型糖尿病

• 批准号: 10252448
• 负责人: Sandro Belvedere
• 金额: $ 58.41万
• 依托单位: FORKHEAD BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10252448
• 关键词: ADME Study; Ablation; Address; Adverse effects; Animals; Area; Artificial Pancreas; Autoimmune; Award; B-Lymphocytes; Beta Cell; Biological Assay; Biological Availability; Biological Response Modifier Therapy; Blood Glucose; Blood Vessels; Caring; Cell Therapy; Cell physiology; Cells; Cessation of life; Chemistry; Chronic; Clinical; Coupled; Data; Development; Devices; Diabetes Mellitus; Diabetic mouse; Disease; Disease Management; Dose; Endocrine; Face; Foundations; Genetic; Glucose; Goals; Health; Human; Hypoglycemia; Immunosuppression; Inbred NOD Mice; Injections; Insulin; Insulin deficiency; Insulin-Dependent Diabetes Mellitus; Intellectual Property; Lead; Licensing; Life; Medical; Medical Care Costs; Modality; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Onset of illness; Oral; Oregon; Organoids; Outcome; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Primates; Procedures; Property; Proteins; Quality of life; Recurrence; Research; Risk; Safety; Sales; Secure; Series; Small Business Innovation Research Grant; Streptozocin; Structure of beta Cell of islet; Structure-Activity Relationship; System; Technology; Testing; Therapeutic; Tissues; Universities; animal efficacy; base; blood glucose regulation; clinical development; clinically translatable; commercial application; cyber security; design; diabetes mellitus therapy; diabetic; economic cost; forkhead protein; gene therapy; glucose monitor; gut endocrine cell; improved; in vivo; inhibitor/antagonist; innovative technologies; lead candidate; lead optimization; mouse model; new technology; nonhuman primate; novel; novel therapeutics; pancreatic juice; patient subsets; phase 1 study; pill; pre-clinical; premature; professor; progenitor; response; safety study; screening; small molecule; small molecule inhibitor; small molecule therapeutics; stem; therapy development; tool; type I and type II diabetes

PROJECT SUMMARY Forkhead BioTherapeutics aims to develop a novel oral therapy for diabetes that will make all insulin therapies obsolete. Over 50 million patients with type 1 diabetes (T1D) or late stage type 2 diabetes (T2D) worldwide require life-long insulin injections. By current standards of care, >50% of the patients fail to meet glucose control goals, leading to vascular complications and premature death. This is largely due to the narrow therapeutic window of insulin and its potential to cause life-threatening hypoglycemia. Novel therapies that replace native pancreatic b cell function, namely, releasing insulin in a glucose-regulated manner, remain a tremendous unmet need. Forkhead Bio’s co-founder Dr. Domenico Accili discovered that genetic ablation of the transcription factor Forkhead box protein O1 (FOXO1) in gut endocrine cells reprograms them into “b-like” cells that secrete insulin in response to glucose. Accili et al. also uncovered several series of small-molecule FOXO1 inhibitors. This body of work delineates a path towards developing an oral FOXO1 inhibitor therapy that converts specific gut cells to replace b cell function. The product of this SBIR will be an oral pill that normalizes glucose control and eliminates the burden of insulin injections and frequent blood glucose checks, thus improving patients’ quality of life, reducing medical costs, and making “insulin-dependent” diabetes a disease of the past. In Phase I, we validated the target pharmacologically, showing that small-molecule FOXO1 inhibitors induce gut b-like cells in mice. In addition, we synthesized >350 novel molecules, established structure-activity relationships, and identified compounds suitable for oral dosing. We also created ex vivo assays critical for assessing clinical translatability, showed evidence for non-human primate (NHP) as an appropriate large animal efficacy model and identified collaborators at the Oregon National Primate Research Center with strong expertise in this area. The significant Phase I results proved the feasibility of our SBIR goal to develop an oral agent that converts b- like cells in the gut to normalize glucose control in both T1D and T2D. In Phase II, we aim to (1) complete lead optimization to identify Lead Candidate molecules with sufficient activity, selectivity, drug-like properties, and tolerability; (2) demonstrate the Lead Candidates’ efficacy in diabetic mouse models; and (3) select one Lead Candidate to demonstrate in vivo gut b-like cell conversion in NHPs. If awarded, this Phase II will accelerate chemistry optimization and enable the demonstration of large-animal translatability for a novel target. Following Phase II, we will perform additional IND-enabling studies and submit an application to the FDA to initiate Phase 1 clinical trials. We have secured intellectual properties including composition of matter claims. Our lead product, likely to be licensed or acquired in preclinical or early clinical stage by a major pharmaceutical company, will be an oral pill that normalizes glucose control and improves quality of life for over 50 million patients with diabetes, with the potential to displace >$30 billion annual sales of insulins.

项目概要 Forkhead BioTherapeutics 旨在开发一种新型口服糖尿病疗法，使所有胰岛素疗法都成为可能 全球有超过 5000 万 1 型糖尿病 (T1D) 或晚期 2 型糖尿病 (T2D) 患者。 需要终生注射胰岛素 根据目前的护理标准，>50% 的患者无法达到血糖控制。 目标，导致血管并发症和过早死亡，这很大程度上是由于治疗范围狭窄。 胰岛素的窗口期及其导致危及生命的低血糖的潜力。 胰腺 B 细胞功能，即以葡萄糖调节的方式释放胰岛素，仍然是一个巨大的未满足的问题 Forkhead Bio 的联合创始人 Domenico Accili 博士发现转录因子的基因消融。 肠道内分泌细胞中的叉头盒蛋白 O1 (FOXO1) 将它们重新编程为分泌胰岛素的“b 样”细胞 Accili 等人还发现了几种小分子 FOXO1 抑制剂。 的工作描绘了开发口服 FOXO1 抑制剂疗法的道路，该疗法可将特定肠道细胞转化为 该 SBIR 的产品将是一种口服药丸，可以使血糖控制正常化并消除 B 细胞功能。 胰岛素注射的负担和频繁的血糖检查，从而改善患者的生活质量， 降低医疗成本，并使“胰岛素依赖型”糖尿病成为过去。 在第一阶段，我们从药理学角度验证了目标，表明小分子 FOXO1 抑制剂可诱导肠道 此外，我们还合成了超过 350 个新分子，建立了结构-活性关系， 并确定了适合口服给药的化合物。我们还创建了对于评估临床至关重要的离体测定。 可翻译性，显示了非人类灵长类动物（NHP）作为合适的大型动物功效模型的证据 并确定了俄勒冈国家灵长类研究中心在该领域拥有丰富专业知识的合作者。 第一阶段的重要结果证明了我们 SBIR 目标的可行性，即开发一种将 b- 就像肠道中的细胞一样，可以使 T1D 和 T2D 的血糖控制正常化。 在第二阶段，我们的目标是 (1) 完成先导化合物优化，以确定具有足够活性的先导候选分子， (2) 证明主要候选药物对糖尿病小鼠的功效 模型；(3) 选择一名主要候选人来证明 NHP 中的体内肠道 B 样细胞转化。 第二阶段将加速化学优化并实现大型动物可翻译性的演示 对于新的目标，我们将在第二阶段之后进行额外的 IND 研究并提交申请。 我们已获得 FDA 的知识产权，以启动第一阶段临床试验。 我们的主导产品可能在临床前或早期临床阶段获得主要产品的许可或收购。 制药公司将推出一种口服药丸，可以使血糖控制正常化并改善生活质量超过 5000 万糖尿病患者，有可能取代胰岛素年销售额超过 300 亿美元。