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.

项目摘要 叉子生物治疗剂旨在开发一种新型的口服糖尿病，以使所有胰岛素疗法 过时的。全球超过5000万患有1型糖尿病（T1D）或晚期2型糖尿病（T2D）的患者 需要终身胰岛素注射。按照目前的护理标准，> 50％的患者无法触及葡萄糖控制 目标，导致血管并发症和过早死亡。这主要是由于狭窄的疗法 胰岛素及其引起威胁生命低血糖的潜力。替代本地的新颖疗法 胰腺B细胞功能，即以葡萄糖调节的方式释放胰岛素，仍然是巨大的未经 需要。 Forkhead Bio的联合创始人Domenico Accili博士发现转录因子的遗传消融 肠内内分泌细胞中的叉子盒蛋白O1（FOXO1）将其重新编程为“ B样”细胞，该细胞秘密胰岛素 响应葡萄糖。 Accili等。还发现了几个系列的小分子FOXO1抑制剂。这个身体 工作描述了开发口服FOXO1抑制剂疗法的途径，该抑制剂将特定的肠道细胞转换为 替换B单元功能。该SBIR的产物将是一种口服药丸，可以使葡萄糖控制并消除 胰岛素注射和经常进行血糖检查的燃烧，从而改善了患者的生活质量， 降低医疗费用，使“胰岛素依赖性”糖尿病仅是过去的疾病。 在第一阶段，我们通过药理学验证了靶标，表明小分子FOXO1抑制剂会影响肠道 小鼠中的B样细胞。此外，我们合成了> 350个新分子，建立的结构活性关系， 并确定适合口服剂量的化合物。我们还创建了对评估临床至关重要的体内测定 可翻译性，显示了非人类灵长类动物（NHP）作为适当的大动物效率模型的证据 并确定了俄勒冈州国家灵长类动物研究中心的合作者，并在该领域具有强大的专业知识。 重要的I阶段结果证明了我们的SBIR目标的可行性，以开发转换B-的口服剂 像肠道中的细胞一样，在T1D和T2D中均标准化葡萄糖。 在第二阶段，我们的目标是（1）完整的铅优化，以鉴定具有足够活性的铅候选分子， 选择性，类似药物的特性和耐受性； （2）演示铅候选者在糖尿病小鼠方面的效率 模型； （3）选择一个铅候选者在NHP中演示体内肠道B样细胞转换。如果被授予 该阶段II将加速化学优化，并能够证明大动物的转换性 对于一个新颖的目标。在第二阶段之后，我们将执行其他辅助研究并提交申请 向FDA启动1期临床试验。我们确保了知识特性，包括 物质主张。我们的主要产品，可能是由主要的临床前或早期临床阶段获得许可或获得的 制药公司将是一种口服药丸，可以使葡萄糖控制归一化并改善过度的生活质量 5000万例糖尿病患者，有可能取代胰岛素的300亿美元。