Monoclonal Antibodies Targeting MMP-9 Alleviate Peripheral Neuropathy in Diabetic Mice

Diabetic peripheral neuropathy (DPN) describes nerve damage in the hands, legs, and feet caused by diabetes. Over time, high levels of blood sugar can injure nerve fibers, with symptoms ranging from numbness, a tingling or burning sensation, muscle weakness, to pain and cramps.

Scientists headed by a team at the University of Texas Health Science Center at Houston have now developed monoclonal antibodies (mAbs) targeting matrix metalloproteinase-9 (MMP-9), which in a newly reported preclinical study slowed and even reversed diabetic nerve damage in mouse models of type I diabetes (T1D) and type II diabetes (T2D). The team suggests that their results bring researchers one step closer to developing a treatment for humans.

Research lead Xin (Alex) Ge, PhD, professor in the Texas Therapeutics Institute at The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases within McGovern Medical School at UTHealth Houston, is senior and co-corresponding author of the team’s published paper in Science Translational Medicine, titled “Monoclonal antibodies inhibiting MMP-9 activity alleviate peripheral neuropathy in diabetic mice.”

Up to 50% of diabetes patients will develop peripheral neuropathy, which is the most common chronic complication of diabetes, the authors wrote. “The hallmark of diabetic peripheral neuropathy (DPN) is the length-dependent damage of peripheral nerves because of impaired microvascular circulation and mitochondrial dysfunction,” they explained. In addition to pain, tingling or numbness, symptoms may include loss of balance, slow wound healing and foot ulcers. However, the team further noted, “Despite its substantial impact, there are currently no effective disease-modifying treatments available to prevent or reverse the progression of nerve damage.”

Ge stated, “There is no good drug for managing peripheral neuropathy. There are painkillers and other drugs, but they are only targeting the symptoms.” For their reported study the investigators focused on the enzyme MMP-9. This enzyme can break down other proteins found between tissues. It is responsible for excess immune response in the peripheral nervous system and disease progression that impairs wound healing. “By regulating neuroinflammation, matrix metalloproteinase-9 (MMP-9) is both sufficient and required for the pathogenesis of neuropathy, representing a promising drug target for DPN,” they commented. “However, small-molecule inhibitors that often lack target specificity.”

Ge and the team instead developed monoclonal antibodies targeting MMP-9. “Developing an antibody that selectively targets MMP-9 has been challenging because MMP-9 is closely related to other enzymes,” acknowledged first author Kibaek Lee, PhD, a postdoctoral research fellow at the Institute of Molecular Medicine. “To overcome this challenge, we combined a camelid-inspired antibody library design with a functional selection approach to identify antibodies that specifically inhibit MMP-9. These new biotechnologies separate our antibodies from others.”

In preclinical tests mice injected with the antibodies regenerated nerve fiber and showed improved wound healing in their paws. “MMP-9 mAbs also reduced epidermal nerve fiber degeneration in diabetic mice by enhancing nerve mitochondrial function and promoting skin angiogenesis,” they stated.

“ This gives us hope that we can not only relieve the symptom, but also reverse the progression of disease,” said Ge, who holds the Kay and Ben Fortson Distinguished Chair in Neurodegenerative Disease Research at McGovern Medical School.

In addition, the team showed also showed that MMP-9 expression in human dorsal root ganglia (DRG) is increased among patients with diabetes. Further human genetic analysis found that both rare and common coding variants in the MMP9 gene are associated with neuropathic pain phenotypes. “The translational relevance of this study is supported by the observation that MMP-9 expression is increased in satellite glial cells and macrophages in the DRG of patients with T2D,” they stated. “Together, these translational findings indicate that MMP-9–specific mAbs hold potential as disease-modifying therapies for peripheral neuropathy and for reducing lower extremity complications associated with diabetes.”