Novel therapeutic for treatment of type 1 diabetes

治疗 1 型糖尿病的新疗法

基本信息

批准号：
9908948
负责人：
David Joseph Maloney
金额：
$ 30万
依托单位：
VERALOX THERAPEUTICS, INC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908948
关键词：
Adult Animal Model Arachidonate 12-Lipoxygenase Arachidonic Acids Asthma Autoantibodies Autoimmune Process Autoimmunity Beta Cell Biological Availability Carbon Cell Death Cell physiology Cells Centers for Disease Control and Prevention (U.S.)Characteristics Childhood Chronic Disease Clinical Trials Collaborations Data Defect Dependence Development Diabetes Mellitus Disease Dose Drug Kinetics Enzymes Excipients Formulation Functional disorder Funding Future Genes Genetic Goals Grant Hour Human Immune Immune system Immunologics Immunotherapy Inbred NOD Mice Incidence Inflammation Injections Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Islets of Langerhans LOX gene Lead Mediating Metabolism Modeling Mus National Institute of Diabetes and Digestive and Kidney Diseases Non obese Obesity Oral Outcome Pancreas Pathogenesis Patients Pharmaceutical Preparations Phase Phenotype Polymers Positioning Attribute Pre-Clinical Model Prediabetes syndrome Property Publishing Reporting Residual state Rodent Model Small Business Innovation Research Grant Small Business Technology Transfer Research Solubility Specificity Streptozocin Testing Toxin Validation Work amorphous solid analytical method aqueous arm candidate selection caspase 14 clinical candidate clinically relevant clinically translatable cytokine diabetic efficacy study efficacy testing first-in-human improved in vivo inhibitor/antagonist insulin dependent diabetes mellitus onset insulitis intraperitoneal islet lymph nodes melting method development mouse model novel novel therapeutic intervention novel therapeutics performance tests pre-clinical preservation prevent protective effect prototype response scale up success

项目摘要

The incidence of type 1 diabetes (T1D) has been increasing in the US for reasons that remain elusive. The Centers for Disease Control and Prevention (CDC) reports that T1D is the third most prevalent chronic disease of childhood in the USA, behind asthma and obesity. Approximately 5% of the 30.3 million adults with diabetes in the USA have T1D. The pathogenesis of T1D encompasses a spectrum that ranges from predominantly aggressive autoimmunity against islet β cells to genetic and acquired defects inherent to β-cell function and survivability. Drugs that block autoimmunity have shown limited success in slowing the destruction of β cells in humans, emphasizing the need to develop new therapies that preserve β cells as an alternative or adjunct to immune-based therapies. The published and preliminary data by Veralox and our academic collaborators present compelling evidence that the enzyme 12-lipoxygenase (12-LOX) in the islet contributes to β cell death and dysfunction in T1D. As a first-in-class 12-LOX inhibitor, VLX-1005 provides a new therapeutic approach to T1D centered on its ability to protect the pancreas from cytokine-induced β cell loss and thus prevent the progression of new onset T1D. A key effect of VLX-1005 is its ability to preserve residual functional β cells in both early and advanced stages of the disease. As a potential future therapy for T1D, an oral formulation of VLX- 1005 would allow for long-term dosing in the pre- or post-diabetic state. The goal of this STTR proposal is to develop our first-in-class 12-LOX inhibitor, VLX-1005, for oral formulation to be tested in a “humanized” non- obese (NOD) mouse model containing replacement of the endogenous mouse enzyme with human 12-LOX. In this proposal, we will achieve the following Aims:Aim 1: Develop an oral formulation of VLX-1005 and conduct mouse pharmacokinetics studies. Aim 2: Determine efficacy of oral VLX-1005 in humanized ALOX12 (hALOX12) non-obese (NOD) mice. The deliverables of this proposal are (1) Development of a clinically-translatable oral formulation that demonstrates improved solubility/re-dissolution characteristics with relevant dose-linear PK characteristics (e.g. T1/2 >2 hours, oral bioavailability (%F) >30%), and (2) Validation that orally administered VLX-1005 engages and inhibits downstream metabolites of pancreas 12-LOX and protects β cells in NOD mice harboring the relevant human 12-LOX enzyme. Successful completion of these aims will position the project for a phase 2 STTR or SBIR grant focused on IND-enabling studies and the immunologic consequences (immune cell subtypes in pancreatic lymph nodes, insulitis) of VLX-1005 treatment in humanized NOD mice.

在美国，1 型糖尿病 (T1D) 的发病率一直在上升，但原因尚不清楚。疾病控制与预防中心 (CDC) 报告称，T1D 是第三大流行的慢性疾病在美国，3030 万成年人中约有 5% 患有糖尿病，仅次于哮喘和肥胖。在美国，T1D 的发病机制主要包括以下范围：针对胰岛 β 细胞的攻击性自身免疫，导致 β 细胞功能固有的遗传和后天缺陷，以及阻断自身免疫的药物在减缓β细胞破坏方面取得的成功有限。人类，强调需要开发新的疗法来保留 β 细胞作为替代或辅助 Veralox 和我们的学术合作者已发表的初步数据。提供了令人信服的证据，证明胰岛中的 12-脂氧合酶 (12-LOX) 有助于 β 细胞死亡作为首创的 12-LOX 抑制剂，VLX-1005 提供了一种新的治疗方法。 T1D 的核心是其保护胰腺免受细胞因子诱导的 β 细胞损失的能力，从而防止 VLX-1005 的一个关键作用是它能够保留残余的功能性 β 细胞。 VLX- 的口服制剂作为 T1D 的未来潜在治疗方法。 1005 允许在糖尿病前期或后期状态下长期用药。该 STTR 提案的目标是：开发我们的一流 12-LOX 抑制剂 VLX-1005，用于口服制剂，并在“人源化”非肥胖 (NOD) 小鼠模型，用人 12-LOX 替代内源性小鼠酶。根据该提案，我们将实现以下目标：目标 1：开发 VLX-1005 的口服制剂并进行小鼠药代动力学研究目标 2：确定口服 VLX-1005 在人源化 ALOX12 (hALOX12) 非肥胖 (NOD) 小鼠中的功效。该提案的可交付成果是 (1) 开发一种可临床转化的口服制剂，表现出改善的溶解度/再溶解特性以及相关的剂量线性 PK 特性（例如 T1/2 > 2 小时，口服生物利用度 (%F) > 30%)，以及 (2) 验证口服 VLX-1005 的作用和抑制胰腺 12-LOX 的下游代谢物并保护含有相关蛋白的 NOD 小鼠的 β 细胞成功完成这些目标将使该项目获得 2 期 STTR 或 SBIR 资助，重点关注 IND 启用研究以及 VLX-1005 治疗的免疫学后果（胰腺淋巴结中的免疫细胞亚型、胰岛炎）。人源化NOD小鼠。