Novel therapeutic for treatment of type 1 diabetes

在美国，1型糖尿病(T1D)的发病率一直在上升，原因仍然难以捉摸。这个 疾病控制和预防中心(CDC)报告称，T1D是第三大最常见的慢性病 在美国，哮喘和肥胖症背后的童年。在3030万成人糖尿病患者中，约有5% 在美国有T1D。T1D的发病机制包括一系列主要的 针对胰岛β细胞的侵袭性自身免疫对β细胞功能固有的遗传和获得性缺陷和 生存能力。阻断自身免疫的药物在减缓β细胞的破坏方面成效有限。 人类，强调需要开发新的疗法来保存β细胞作为替代或附属于 基于免疫的疗法。Veralox和我们的学术合作者发布的和初步的数据 目前令人信服的证据表明，胰岛中的12-脂氧合酶(12-LOX)酶与β细胞死亡有关 和T1D功能障碍。作为一种一流的12-LOX抑制剂，VLX-1005提供了一种新的治疗方法 T1D的核心是保护胰腺免受细胞因子诱导的β细胞丢失的影响，从而防止 新发T1D的进展。VLX-1005的一个关键作用是它能够保存残留的功能性β细胞 包括疾病的早期和晚期。作为T1D的潜在未来治疗方法，VLX的口服制剂- 1005将允许在糖尿病前或糖尿病后状态下长期服用。这项STTR提案的目标是 开发我们首屈一指的12-LOX抑制剂VLX-1005，用于口服配方，在“人性化”的非 肥胖(NOD)小鼠模型，包含用人12-LOX替换内源性小鼠酶。在……里面 目标1：研制VLX-1005口服制剂，并进行小鼠药代动力学研究。目的：观察口服VLX-1005对人源化ALOX12(HALOX12)非肥胖(NOD)小鼠的疗效。这项建议的成果是(1)开发临床可翻译的口服配方， 通过相关的剂量线性PK特性(例如 T1/2&gt；2小时，口服生物利用度(%F)&gt；30%)，以及(2)口服VLX-1005参与和 抑制胰腺12-LOX下游代谢产物并保护携带相关基因的NOD小鼠的β细胞 人12-LOX酶。这些目标的成功完成将使该项目处于第二阶段STTR或SBIR赠款，重点是IND使能研究和VLX-1005治疗人源化NOD小鼠的免疫学后果(胰腺淋巴结中的免疫细胞亚型，岛炎)。

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.