Harnessing bioinformatics to fast-track the discovery of spinal cord injury drug

Spinal cord injury (SCI) remains a major unmet medical challenge, often resulting in permanent paralysis and disability with no effective treatments. Now, researchers at University of California San Diego School of Medicine have harnessed bioinformatics to fast-track the discovery of a promising new drug for SCI. The results will also make it easier for researchers around the world to translate their discoveries into treatments.

One of the reasons SCI results in permanent disability is that the neurons that form our brain and spinal cord cannot effectively regenerate. Encouraging neurons to regenerate with drugs offers a promising possibility for treating these severe injuries. 

The researchers found that under specific experimental conditions, some mouse neurons activate a specific pattern of genes related to neuronal growth and regeneration. To translate this fundamental discovery into a treatment, the researchers used data-driven bioinformatics approaches to compare their pattern to a vast database of compounds, looking for drugs that could activate these same genes and trigger neurons to regenerate. 

Their approach identified Thiorphan - a drug previously tested in humans for non-neurological conditions - as a top candidate. The researchers successfully tested Thiorphan in adult human brain cells, finding that it increased neurite outgrowth, a key metric of regeneration. Being able to confirm that the drug works in adult human brain cells is a significant technical achievement, as brain cells are notoriously difficult to culture in the lab, making them virtually impossible to study in culture dishes. 

The researchers also tested the drug in rats with SCI, finding that when combined with neural stem cell grafts, Thiorphan led to significant improvements in hand function and an increase in neuronal regeneration into the injury site. Rats treated with Thiorphan alone had a 50% increase in recovery of hand function after SCI compared to untreated animals, and another 50% improvement in hand function when Thiorphan was combined with a neural stem cell implant. The researchers are now considering combining Thiorphan with stem cell technology in clinical trials that are planned for the near future.

We were very happy to see that a drug that worked on cells in culture also showed effectiveness in an actual animal model of spinal cord injury. This is not always the case in new drug development."

Erna van Niekerk, Ph.D., assistant project scientist, Department of Neurosciences at UC San Diego School of Medicine and lead author of the study

The identification of Thiorphan as a potentially effective treatment for SCI resulted from "a convergence of technologies," according to van Niekerk. "Gene sequencing, computational bioinformatics, and cell culture all came together to rapidly identify a potentially useful treatment that might have taken decades before these convergent technologies were available."

Because it has already undergone safety testing in humans, Thiorphan could quickly advance into clinical trials for SCI. The study exemplifies how technology can accelerate drug discovery by breathing new life into shelved drugs that have already been tested for other diseases. 

Mark H. Tuszynski, M.D., professor in the Department of Neurosciences at UC San Diego and senior author of the study, stated, "We succeeded in culturing adult human brain cells in large numbers in this study, offering a powerful new tool for the discovery of treatments for neurological disorders. These are not stem cells; they are adult brain cells that previously were not possible to culture. The ability to culture adult brain cells could be useful for testing new drugs or gene therapies for many brain diseases."

According to van Niekerk, moving Thiorphan forward to clinical testing is an important next step. "We are making efforts now to optimize Thiorphan for future clinical trials, a task simplified by the fact that the drug has already been used safely in people."

The study was published in Nature and funded, in part, by the Adelson Medical Research Foundation, the Veterans Administration, the National Institutes of Health, and Wings for Life.