Reactive oxygen species (ROS) are constitutively generated in cells and are required to sustain numerous physiologic processes. Generally, ROS mediate cellular signaling; however, when the balance between ROS production and scavenging is disrupted, they cause oxidative stress resulting in tissue injury. Excessive ROS production has been implicated in various disease processes, including diabetic nephropathy, hypertensive nephropathy, atherosclerosis and diabetic retinopathy. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Noxs) catalyze electron transfer from NADPH to molecular oxygen and are the major sources of ROS. Seven Nox (NADPH oxidase) isozymes are expressed in a wide variety of animal cell types either exclusively or in combination. We have developed new screening system in drosophila. Drosophila line enable us to get easily over expressing each human Nox enzymes. And we can do enzyme activity interfering test for each of the isozymes such as nox1, nox2, nox4, nox5 and doux. Due to the skipping protein purification step, screening is very much cost effective and quick. For the high through put system it will supply good result with low cost.
The beauty of NOX inhibitor.
The sole function of Nox enzymes is to produce Reactive Oxygen Species, which can cause tissue damage and modification of cell function. The NOX enzymes play an important role in maintaining normal physiological function, but under various conditions they may become over expressed with increased production of ROS leading to disease. Targeting Nox enzymes may lead to more effective inhibition of oxidative stress related diseases as they address the source of the ROS.
AptaBio has a unique and proprietary screening platform and pipeline with a first in class drug candidate, APX115 to treat diabetic nephropathy (DN). In parallel, AptaBio is using its Nox platform to develop new inhibitor, APX-5278, APX-1004 with different Nox selectivity which can address atherosclerosis and retinopathy.
And, AptaBio developing another pipeline product, APX-311 which can address Nonalcoholic steatohepatitis (NASH) therapy.
Disease : Diabetic Nephropathy
Status : Phase 1.
APX-115 is an orally available small molecule which has good bioavailability, biostability and low toxicity. APX-115 is a potent pan Nox inhibitor which has recently been selected as a clinical development and now we are processing clinical phase 1 study.
A novel compound, APX-115 exerts a renoprotective effect in type 1 and 2 diabetic mice. In the kidney, APX-115 attenuated Nox gene upregulation and protein expression while improving inflammatory and fibrotic processes. Pharmacologically pan Nox inhibitors, APX-115 effectively reduced systemic oxidative stress, albuminuria, and kidney fibrosis in mouse models of type 1 and type 2 diabetic nephropathy.
APX-115 significantly improved insulin resistance in diabetic mice. Oxidative stress as measured by plasma 8-isoprostane level was decreased in the APX-115 group compared with diabetic controls. All lipid profiles, both in plasma and tissues improved with Nox inhibition. APX-115 decreased urinary albumin excretion and preserved creatinine level. In diabetic kidneys, APX-115 significantly improved mesangial expansion.
(Laboratory Investigation (2017), 1-13 doi: 10.1038/labinvest.2017.2)
Oxidative stress has emerged as a critical pathogenic factor in the initiation and development of diabetic complications. And diabetic nephropathy is kidney disease or damage that is a common complication of diabetes. Worldwide, approximately 150 million people are living with diabetes and the global burden is expected to double between 2000 and 2030. Complications add greatly to the already substantial costs of medical care for patients with type 2 diabetes. In the US, diabetic kidney disease occurs in approximately over 90 percent of all patients with diabetes.
Disease : Atherosclerosis
Status : Preclinical
Reactive oxygen species (ROS) play a key role in the pathogenesis of atherosclerosis. The main mechanisms which are involved are low-density lipoprotein oxidative modification, inactivation of nitric oxide and modulation of redox-sensitive signaling pathways. ROS contribute to several aspects of atherosclerosis including endothelial cell dysfunction, monocyte/macrophage recruitment and activation, stimulation of inflammation, and inducing smooth muscle cell migration and proliferation. NADPH oxidase is the main source of ROS in the vasculature. (Postepy Hig Med Dosw (Online). 2017, Jan 28;71(0):57-68.)
Disease : Diabetic Retinopathy, AMD
Status : Preclinical
Diabetic retinopathy (DR) is one of the main complications in patients with diabetes and has been the leading cause of visual loss since 1990. Oxidative stress is a biological process resulting from excessive production of reactive oxygen species (ROS). This process contributes to the development of many diseases and disease complications. ROS interact with various cellular components to induce cell injury. (Redox Report, 22:1, 10-16)
Disease : Nonalcoholic steatohepatitis (NASH)
Status : Preclinical
NASH is the more aggressive subtype of NAFLD and may replace hepatitis C as the leading cause of liver transplantation by 2020. The presence of fibrosis is the strongest predictor of mortality in patients with this disease. Beside lifestyle changes, there are no FDA-approved medications for patients with NASH, the need to find appropriate therapeutic targets is now more urgent than ever before. (Liver International 2017; 37(Suppl.1) : 97-103)