Spinal cord injuries caused by external trauma, such as traffic accidents or falls, often lead to the permanent loss of motor and sensory functions. This is because the spinal cord—the central pathway connecting the brain and the rest of the body—harbors a “brake” mechanism that halts repair. For the first time, the molecular mechanism behind this braking system has been revealed.

A research team led by Director C. Justin LEE of the Center for Cognition and Sociality at the Institute for Basic Science (IBS), in collaboration with Professor HA Yoon of Yonsei University College of Medicine, identified that the inhibitory neurotransmitter GABA, produced by astrocytes in the spinal cord through the enzyme monoamine oxidase B (MAOB), is the key factor that blocks recovery after spinal cord injury. Furthermore, they demonstrated the therapeutic potential of targeting this pathway by showing that MAOB inhibition promotes spinal cord repair.

Until now, recovery failure after spinal cord injury has largely been attributed to the formation of the so-called glial barrier. This barrier, formed by the rapid proliferation of astrocytes and other glial cells around the lesion, protects the injury site in the acute phase but later prevents axonal regrowth. However, the precise molecular mechanism hindering regeneration remained unclear. As a result, existing treatments for spinal cord injury have primarily focused on suppressing inflammation or alleviating symptoms, rather than directly addressing neural repair.

Building on their earlier work, which showed that reactive astrocytes abnormally produce GABA via MAOB and exacerbate neurodegenerative diseases such as Alzheimer’s, the team investigated whether a similar mechanism occurs in spinal cord injury. They found that GABA suppresses the expression of BDNF (a key neurotrophic factor) and its receptor TrkB, both essential for neuronal regeneration. Consequently, the production of GABA acts as a molecular brake, shutting down growth signals and blocking axonal regrowth and functional recovery after injury.

To validate this, the researchers used animal models in which MAOB expression in spinal astrocytes was either suppressed or enhanced. Inhibition of MAOB allowed axons to regrow and restored hindlimb motor function, while increased MAOB expression led to severe tissue loss and almost no functional recovery. These findings confirmed that the MAOB–GABA pathway directly prevents spinal cord regeneration.

The team further tested the MAOB inhibitor KDS2010 in animal models of spinal cord injury. Treated mice showed significant improvements in locomotion, such as fewer hindlimb slips in ladder-walking tests, and exhibited robust axonal regrowth at the injury site. Histological analyses revealed reduced lesion cavities and increased remyelinated axons. Importantly, similar benefits were confirmed in non-human primates, where tissue preservation and neural protection were markedly improved. The safety and tolerability of KDS2010 had already been validated in a Phase I clinical trial in healthy adults, underscoring its potential as a therapeutic candidate.

Director C. Justin LEE of IBS stated, “This study identifies a direct molecular pathway that suppresses neural regeneration after spinal cord injury and presents a strategy to overcome it. Unlike existing treatments, this offers a fundamentally new therapeutic approach. The multi-level validation in rodents, primates, and Phase I clinical trials provides strong evidence that this drug candidate could translate into real treatment for patients.”

Professor HA Yoon of Yonsei University College of Medicine added, “KDS2010 has already demonstrated safety in a Phase I clinical trial, and we plan to proceed with Phase II trials to evaluate its efficacy in spinal cord injury patients. Moreover, we aim to investigate whether the MAOB–GABA pathway plays a role in other neurological disorders, broadening its potential applications into a more comprehensive therapeutic platform.”

This research was carried out through multi-institutional collaboration involving IBS, Yonsei University, Seoul National University, the Korea Institute of Science and Technology (KIST), and Neurobiogen, with support from the Ministry of Science and ICT and the National Research Foundation of Korea. The findings were published on September 11 in Signal Transduction and Targeted Therapy (Impact Factor 52.7, 2024 JCR), a globally influential journal covering both basic and translational biomedical sciences.

Figure 1. Therapeutic effects of KDS2010 in an animal model of spinal cord injury
The selective MAOB inhibitor KDS2010 significantly improved functional recovery in a spinal cord injury animal model. Treated animals showed marked restoration of behavioral scores and locomotor abilities, and these effects were sustained over time (b, d). While control animals with injury alone exhibited severe hindlimb paralysis, the KDS2010-treated group demonstrated clear recovery of motor function and improved walking performance. In particular, gait analysis using an automated locomotion assessment system revealed near-normal motor performance (e).

Figure 2. Neuroprotective and tissue-restorative effects of KDS2010
In the spinal cord injury animal model, administration of KDS2010 suppressed the injury-induced overexpression of MAOB in astrocytes and restored the expression of MAP2, a neuronal marker protein, thereby preserving neurons at the lesion site (a). Electron microscopy further revealed that demyelinated and disrupted axons were restored to near-normal myelinated structures (b–c). Quantitative g-ratio analysis confirmed that the abnormally thinned myelin was significantly thickened following treatment (d).

Figure 3. Functional and molecular recovery effects of KDS2010
Electrophysiological analyses showed that spinal cord injury led to an excessive increase in tonic GABA currents (persistent inhibitory signaling), which were restored to normal levels after KDS2010 administration, thereby re-establishing excitatory–inhibitory balance between neurons (a). At the molecular level, KDS2010 reduced aberrant GABA production from astrocytes while simultaneously increasing the expression of proBDNF (a precursor of brain-derived neurotrophic factor), thereby shifting the injured spinal cord environment toward a state favorable for neural regeneration (b).

Figure 4. Phase I pharmacokinetic (PK) results of KDS2010
The pharmacokinetic properties of KDS2010 were evaluated in a Phase I clinical trial in healthy adults. In the single-dose study (a), plasma concentrations increased proportionally with escalating doses ranging from 30 mg to 960 mg, followed by a gradual decline with a consistent half-life. In the multiple-dose study (b), stepwise dose escalation from 60 mg to 480 mg demonstrated stable and predictable PK profiles. Even at higher doses, drug concentrations remained within the safe range. These results indicate that KDS2010 exhibits dose-proportional pharmacokinetics and a favorable safety profile, supporting its potential progression to Phase II clinical trials in spinal cord injury patients.