Existing Drug Thiorphan Reprograms Injured Neurons, Boosting Spinal Cord Recovery

Major Breakthrough: Repurposed Drug Promotes Functional Recovery After Spinal Cord Injury

A groundbreaking study published in the journal Nature in 2025 has unveiled a promising new therapeutic strategy for spinal cord injury (SCI) recovery. Researchers demonstrated that the existing drug Thiorphan can effectively reprogram injured neurons, activating their intrinsic regenerative capacity and leading to significant functional recovery in animal models.

This discovery is particularly impactful because Thiorphan, or its close analogs, are already known compounds with established safety profiles in humans, potentially accelerating the timeline for clinical trials. The findings offer a tangible pathway toward restoring motor and sensory function for individuals living with paralysis caused by SCI.

The Challenge of Spinal Cord Injury and Neuronal Regeneration

Spinal cord injuries are devastating because they sever the corticospinal tract (CST), the primary pathway connecting the brain’s motor cortex to the spinal cord. Unlike peripheral nerves, neurons in the central nervous system (CNS) typically fail to regenerate after injury due to both inhibitory factors in the injury site and a decline in the neurons’ intrinsic growth capacity.

For decades, research has focused on overcoming the inhibitory environment. However, this new approach targets the neurons themselves, essentially flipping a switch to restore their ability to grow and repair the damaged connections.

How Thiorphan Reprograms the Brain-Spinal Pathway

The research team utilized a sophisticated, multi-step pipeline to identify compounds that could enhance neural repair. This process involved characterizing the transcriptomic profile (the complete set of RNA transcripts) of injured CST neurons to understand which genes were suppressed following trauma. They then screened thousands of compounds capable of reversing this suppression.

Thiorphan emerged as the leading candidate. Its mechanism of action centers on inhibiting the enzyme neprilysin (NEP). NEP is a metalloprotease that plays a role in regulating the activity of various neuropeptides. By inhibiting NEP, Thiorphan triggers a cascade of molecular events within the injured neurons, effectively activating their dormant intrinsic growth programs.

This activation leads to several critical outcomes:

• Upregulation of Growth Genes: Thiorphan promotes the expression of genes associated with axon outgrowth and regeneration.
• Axonal Sprouting: The drug encourages the injured CST axons to sprout and extend past the lesion site.
• Synaptic Plasticity: It enhances the ability of the remaining neural circuits to reorganize and form new functional connections below the injury.

Functional Recovery: Beyond Structural Repair

The true measure of success in SCI research is not just structural regeneration, but the return of functional ability. In animal models (typically mice or rats) treated with Thiorphan, the results were highly encouraging, demonstrating significant improvements in motor control.

Key functional recoveries observed included:

• Improved Locomotion: Treated animals showed enhanced coordination and gait stability, indicating better control over walking.
• Enhanced Fine Motor Skills: Crucially, the animals exhibited improved grasping ability and dexterity, suggesting the regeneration of circuits responsible for complex movements.

This functional restoration underscores the potential of Thiorphan to not only encourage axons to cross the injury gap but also to ensure they reconnect meaningfully with the appropriate targets in the spinal cord below the lesion.

“This study provides compelling evidence that targeting the intrinsic regenerative capacity of injured neurons, rather than solely focusing on the inhibitory environment, is a viable and powerful therapeutic strategy,” stated a spokesperson for the research team. “The functional gains we observed suggest that Thiorphan could be a game-changer in accelerating recovery for SCI patients.”

The Advantage of Repurposing an Existing Drug

One of the most exciting aspects of this research is the use of Thiorphan, a compound that is structurally similar to drugs already used clinically for other conditions (such as racecadotril, which is used to treat acute diarrhea). This is a significant advantage in the drug development pipeline.

Developing a completely novel drug can take over a decade and cost billions of dollars, requiring extensive safety and toxicity testing. By repurposing an existing drug with known safety data, researchers can bypass many of the initial preclinical hurdles, potentially moving to human clinical trials much faster—a process known as drug repurposing.

Next Steps Toward Clinical Trials

While the results are highly promising, the research remains in the preclinical stage. The next critical steps involve:

1. Confirmation in Larger Models: Validating the efficacy and safety of Thiorphan in larger animal models that more closely mimic human SCI.
2. Dosage Optimization: Determining the optimal dose and administration route for human application.
3. Initiating Phase I Trials: Seeking regulatory approval to begin Phase I human clinical trials, focusing initially on safety and tolerability in patients with chronic SCI.

Experts caution that while this is a major scientific leap, the path to widespread clinical availability still requires rigorous testing. However, the mechanism—reprogramming the neuron itself—represents a fundamental shift in how the medical community approaches CNS repair.

Key Takeaways

This breakthrough study offers significant hope for the SCI community by demonstrating a novel, effective therapeutic approach:

• Drug Identified: The existing drug Thiorphan was found to promote neural repair after spinal cord injury.
• Mechanism: Thiorphan inhibits the enzyme neprilysin (NEP), activating the intrinsic growth programs of injured corticospinal tract (CST) neurons.
• Efficacy: Treatment resulted in substantial functional recovery in animal models, including improved walking and grasping ability.
• Clinical Potential: Because Thiorphan is a known compound, its path to human clinical trials is expected to be significantly faster than that of a novel drug.
• Future Focus: Research will now concentrate on translating these findings into safe and effective treatments for human patients, starting with clinical trials in the near future.

Conclusion: A New Era for CNS Regeneration

The successful use of Thiorphan to promote functional recovery marks a pivotal moment in regenerative medicine. By demonstrating that the injured central nervous system neurons retain the capacity for regeneration if properly stimulated, the research opens the door to a new generation of treatments focused on molecular reprogramming. This work, published in Nature, solidifies the potential of drug repurposing to rapidly deliver complex scientific breakthroughs from the lab bench to the patient bedside, offering renewed hope for individuals seeking recovery from spinal cord injuries.