Spinal cord injuries are devastating, often resulting in permanent loss of motor and sensory functions. The spinal cord acts as a central pathway connecting the brain to the rest of the body, but it harbors a “brake” mechanism that inhibits repair. The molecular mechanism behind this braking system has recently been discovered by a research team led by Director C. Justin Lee of the Institute for Basic Science (IBS) and Professor Ha Yoon of Yonsei University College of Medicine.
The team found that the inhibitory neurotransmitter GABA, produced by astrocytes in the spinal cord through the enzyme monoamine oxidase B (MAOB), plays a crucial role in blocking recovery after spinal cord injury. By targeting this pathway and inhibiting MAOB, the researchers demonstrated that spinal cord repair can be promoted. This groundbreaking work was published in the journal Signal Transduction and Targeted Therapy.
Traditionally, recovery failure after spinal cord injury has been attributed to the formation of a glial barrier, which prevents axonal regrowth. However, the specific molecular mechanism hindering regeneration had remained unclear until now. The team’s research revealed that GABA suppresses the expression of key factors for neuronal regeneration, such as BDNF and its receptor TrkB, effectively acting as a molecular brake that inhibits axonal regrowth and functional recovery.
Using animal models, the researchers validated their findings by suppressing or enhancing MAOB expression in spinal astrocytes. Inhibition of MAOB resulted in axon regrowth and restored motor function, while increased MAOB expression led to severe tissue loss and hindered recovery. These experiments confirmed that the MAOB-GABA pathway directly prevents spinal cord regeneration.
Furthermore, the team tested the MAOB inhibitor KDS2010 in animal models of spinal cord injury and observed significant improvements in locomotion and axonal regrowth at the injury site. These promising results were also replicated in non-human primates, highlighting the therapeutic potential of KDS2010. The safety and tolerability of this inhibitor have been validated in Phase I clinical trials in healthy adults, underscoring its potential as a treatment for spinal cord injury patients.
Director C. Justin Lee emphasized the significance of this study, stating that it offers a fundamentally new therapeutic approach for spinal cord injuries. He highlighted the multi-level validation in rodents, primates, and clinical trials, providing strong evidence for the translation of this drug candidate into real treatments for patients. Professor Ha Yoon added that Phase II trials are planned to evaluate the efficacy of KDS2010 in spinal cord injury patients and explore its potential applications in other neurological disorders.
This groundbreaking research opens new possibilities for spinal cord injury treatment and offers hope for patients suffering from these debilitating injuries. The study sheds light on a previously unknown molecular pathway that suppresses neural regeneration and provides a promising strategy to overcome it.
