Monoclonal antibodies inhibiting MMP-9 activity alleviate peripheral neuropathy in diabetic mice

Diabetic peripheral neuropathy (DPN) is a debilitating medical condition that affects millions of individuals, causing neuropathic pain and chronic wounds. Despite its substantial impact, there are currently no effective disease-modifying treatments available to prevent or reverse the progression of nerve damage. 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; however, small-molecule inhibitors often lack target specificity. We developed a panel of selective, potent, and proteolytically stable monoclonal antibodies (mAbs) that inhibit MMP-9 activity as a treatment for DPN. We found that systematic administration of MMP-9 inhibitory mAbs alleviated mechanical and cold pain symptoms in diabetic mouse models and restored hind paw wound healing in diabetic mice. MMP-9 mAbs also reduced epidermal nerve fiber degeneration in diabetic mice by enhancing nerve mitochondrial function and promoting skin angiogenesis. Furthermore, we determined that MMP-9 expression in human dorsal root ganglia is increased among patients with diabetes, and human genetic analysis revealed that both rare coding of MMP9 and its common variants are associated with neuropathic pain phenotypes. 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.