Monoclonal Antibody-Based Therapeutics for Targeting MMPs and Diabetic Neuropathy
Abstract
According to a recent report by Centers for Disease Control and Prevention (CDC), more than 120 million U.S. adults are now living with diabetes or prediabetes. Around 34.2 million Americans – 10.5% of the U.S. population – have diabetes. Another 88 million have prediabetes (34.5% of the adult U.S. population), a condition that if not treated often leads to diabetes within 5 years. Medical survey of U.S. military indicates a similar occurrence rate for service personnel and considerably higher ones for veterans. Diabetes is a long-term disease featured by high levels of blood sugar, which itself can often be symptomless. However, diabetes causes many serious complications. The most common one is nerve damage-associated diabetic peripheral neuropathy (DPN), which is estimated to affect up to 50% of people with diabetes. Diabetic neuropathy can cause numbness or tingling in fingers, toes, hands, and feet. Another symptom is a burning, sharp, or aching pain. The pain may be mild at first, but it can get worse over time and spread up to legs or arms. DPN also damages motor nerves that control muscles and causes loss of balance. Although devastating, currently there is no effective treatment for preventing or stopping the nerve damages caused by diabetes. Mounting evidence suggests that neuroinflammation, a localized inflammation in the peripheral and central nervous system, plays a critical role in the development of diabetic neuropathy. When fighting infections of outside invaders, such as bacteria and viruses, acute inflammation as a response of body’s defense system is beneficial. However, prolonged inflammation or chronic inflammation can backfire to damage healthy cells, tissues, and organs. In the cases of diabetes, long-term high blood sugar triggers neuroinflammation, and neuroinflammation leads to self-damages including loss of peripheral nerves. Biomedical studies from many groups, including ours, have pinpointed that certain enzymes called matrix metalloproteinases, or MMPs in short, accelerate the process of such nerve damages. More specially, MMP-9 initiates the pain development and MMP-2 makes the pain more persistent. Therefore, specific inhibition of these MMPs as a potential therapy gives us a hope to treat diabetic neuropathy. Since the 1990s, big pharm companies have invested tremendous efforts and developed dozens of small molecule chemical compounds to inhibit MMPs. Unfortunately, none of these compounds passed clinical trials due to severe side effects such as liver toxicity caused by non-specific inhibition to other human enzymes. To solve this problem, in the last 5 years we have developed novel MMP inhibitors based on monoclonal antibodies (mAbs), which give exceptionally high selectivity. We have also validated that our mAb inhibitors can produce significant relief of neuropathic pain symptoms in mouse models of type 1 diabetes. Notably, multiple mAbs have been approved by the U.S. Food and Drug Administration (FDA) to treat migraine and headaches. This proposed research aims to further develop, optimize, and evaluate mAb inhibitors of MMPs. We will expand to study both type 1 and type 2 diabetes in mouse models as the latter accounts for ~90% of diabetic patients. We will also test our mAb therapeutics for effects on pain relief and protection of sensory function deficits. Our synergic team is composed of a mAb discovery lab at University of California (Riverside campus) and a neuropathic pain research lab at Duke University. We propose to couple in vivo efficacy tests in animal models with mAb discovery at early stage, a unique and highly effective strategy to improve the successful rate of therapeutic development. Overall, diabetes affects millions of Americans including U.S. military personnel. Diabetes-associated nerve damage is the most common and devastating diabetic complication, yet no effective treatment is available. This proposed research plans to develop therapeutic mAbs to dir
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110756
Entities
People
- Ru-Rong Ji
Organizations
- Duke University
- United States Army