Antibody Treatment Reverses Diabetic Nerve Pain in Mice

While the main concern with diabetes is too much glucose in the blood, the condition has a long list of additional complications, which at first glance have little connection to one another. High blood pressure, heart disease, and infections put a significant burden on patients with diabetes, but diabetic neuropathy is one of the condition’s most severe effects. High blood sugar damages nerves throughout the body but most commonly in the legs and feet. Patients experience cramps, pain, tingling, numbness, and burning in affected areas. In severe cases, the condition can lead to amputation. Diabetic neuropathy will affect roughly half of people living with diabetes.¹

Now, in a new study, researchers identified potent and highly specific monoclonal antibodies that slowed and even reversed diabetic neuropathy symptoms in mice. In some animals, researchers even reversed symptoms using an array of antibodies that blocked an inflammatory molecule at the heart of neuropathy. The research was published in Science Translational Medicine.²

The findings could help treat patients with limited options. “There is no good drug for managing peripheral neuropathy,” said Xin (Alex) Ge, a neurobiologist at the University of Texas Health Science Center at Houston, in a statement. “There are painkillers and other drugs, but they are only targeting the symptoms.”

A Monoclonal Antibody Approach to Matrix Metalloproteinase-9

Ge’s team had a molecule known to be involved in the neuroinflammatory processes that kickstart neuropathy called matrix metalloproteinase-9 (MMP-9) in their sights. Even though drug developers have known about the importance of MMP-9 for years, hitting the mark and treating neuropathy has proved extremely difficult. “Developing an antibody that selectively targets MMP-9 has been challenging because MMP-9 is closely related to other enzymes,” said Kibaek Lee, a biochemical engineer in Ge’s lab who coauthored the paper, in the statement. Previous trials that targeted MMP-9 with broad-spectrum compounds had low efficacy and provoked a range of severe side effects, including liver damage.³

Ge’s team set out to identify monoclonal antibodies specific enough to MMP-9 to suppress the molecule without these side effects. Rather than simply assessing how well potential antibodies bound to their target, the scientists used a functional selection approach to whittle down 1.7 billion candidate antibody fragments. This approach relied on E. coli bacteria that had been modified to die in the presence of MMP-9. The researchers first exposed the bacteria to antibody fragments and then added MMP-9 to the mix. Only bacteria exposed to antibodies that could functionally suppress MMP-9 survived. They identified three candidates, two of which bound to the mouse version of MMP-9.

Next, they tested their candidates in mice. Injecting these antibodies into a mouse model of diabetes decreased the animals’ excessive sensitivity to pain and enhanced their wound healing, which their diabetes had impaired. At the cellular level, one of the identified antibodies improved nerve regeneration in the mice and corrected mitochondrial dysfunction, which is commonly seen in diabetic neuropathy.

These findings would have little meaning for diabetic patients if there were no good reason to think they could be replicated in humans. Ge’s team studied samples of dorsal root ganglia—key hubs of the nervous system that interpret sensory information from the extremities—from both diabetic and healthy donors. MMP-9 was significantly elevated in diabetic patients’ nervous systems. A subsequent test in human blood cells showed that the MMP-9 monoclonal antibodies slashed the levels of a series of pro-inflammatory molecules, raising hopes that they could be a potential treatment that could work in humans. “This gives us hope that we can not only relieve the symptom, but also reverse the progression of disease,” Ge said.