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

Abstract

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 <i>MMP9</i> 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.