RGMa administration improves dexterity following spinal cord injury in monkeys
Spinal cord injury, or SCI, damages motor function and frequently leaves the patient paralyzed. A major reason is that the body cannot regenerate the lost neural connections.
In a report in Cerebral Cortex , Kyoto University researchers report that treatment with an antibody for repulsive guidance molecule-a (RGMa) leads to recovered motor function in rhesus monkeys that had experienced SCI, suggesting that a similar antibody treatment could benefit humans.
"The mature mammalian central nervous system has a limited capacity to grow or regenerate because of inhibitor factors," says Kyoto University's Masahiko Takada, who has been investigating the inhibitory factor RGMa in the primate central nervous system. RGMa is naturally expressed by immune and inflammatory cells that localize on traumatized spinal cord regions.
Suppressing RGMa, he continues, has been shown to be effective at promoting axonal growth in rodents with SCI, but "the mechanisms that lead to the recovery of motor functions may differ in higher primates."
The team surgically induced SCI in 12 rhesus monkeys, while continuously delivering an RGMa antibody to one group for four weeks. Following these procedures, all the monkeys performed a series of dexterity tasks.
One such task was to take food pellets out of vertical or horizontal slots. Those that received the antibody treatment showed almost full recovery when challenged with vertical slots, as though they had never undergone SCI. But while they could perform better than untreated monkeys when challenged with horizontal slots, the performance did not match pre-SCI levels.
Subsequent neuroanatomical study indicated that the antibody treatment promoted axon growth in certain regions of the spinal cord.
"In antibody-treated monkeys we found that sprouting corticospinal tract fibers penetrated into laminae VII and IX, where spinal interneurons and motor neurons are located. This shows that the contralesional motor cortex is significantly involved in recovery," notes Takada. Laminae VII and IX, he adds, are below the SCI lesion site and include motor neurons crucial for manual dexterity.
What remains unclear, however, is how the axons released from the RGMa suppression know how to reach these regions. Considering that the antibody was delivered directly into the brain for four weeks, clarifying uncertainties about the recovery mechanism and a more practical delivery system will be required before RGMa antibodies can be considered for human treatment.
Hiroshi Nakagawa, Taihei Ninomiya, Toshihide Yamashita, Masahiko Takada (2018). Treatment With the Neutralizing Antibody Against Repulsive Guidance Molecule-a Promotes Recovery From Impaired Manual Dexterity in a Primate Model of Spinal Cord Injury. Cerebral Cortex.