Novel therapeutic for treatment of type 1 diabetes

点击翻译按钮获取中文摘要

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.