Using bioinformatics to speed discovery of spinal cord injury treatments

Spinal cord injury (SCI) remains a major unsolved medical challenge, often resulting in permanent paralysis and disability without effective treatments. Now, researchers at the University of California, San Diego School of Medicine are using bioinformatics to rapidly discover promising new drugs for SCI. The results will make it easier for researchers around the world to translate their discoveries into treatments.

One reason SCI results in permanent disability is that the neurons that form the brain and spinal cord cannot regenerate effectively. Using drugs to stimulate neuron regeneration offers a promising possibility for treating these severe injuries.

The researchers found that under certain experimental conditions, some mouse neurons activate a specific pattern of genes associated with neuron growth and regeneration. To translate this fundamental discovery into therapy, the researchers used a data-driven bioinformatics approach to compare the patterns to a vast database of compounds, looking for drugs that could activate the same genes and cause neuron regeneration.

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 brain cells and found that it increased neurite outgrowth, an important indicator of regeneration. Confirming that the drug works in adult brain cells is a major technological achievement, as brain cells are notoriously difficult to grow in the lab and virtually impossible to study in a culture dish.

The researchers also tested the drug in rats with SCI and found that when combined with neural stem cell grafts, thiorphan significantly improved hand function and increased nerve cell regeneration to the injury site. Rats treated with thiorphan alone had a 50% increase in recovery of hand function after SCI compared to untreated rats, and combining thiorphan with neural stem cell implants improved hand function by an additional 50%. Researchers are currently considering combining thiorphan with stem cell technology in clinical trials planned for the near future.

We were very pleased to see that a drug that acts on cultured cells also showed efficacy in an actual animal model of spinal cord injury. This is not always the case in new drug development. ”

Dr. Erna van Niekerk, Assistant Project Scientist, Department of Neuroscience, University of California, San Diego School of Medicine, and lead author of the study

According to van Niekerk, thiorphan was identified as a potentially effective treatment for SCI through a “fusion of technologies.” “Gene sequencing, computational bioinformatics, and cell culture have all worked together to rapidly identify potentially useful treatments, but it may have taken decades for these integrated technologies to become available.”

Because it has already been tested for safety in humans, thiorphan could soon advance to clinical trials for spinal cord injuries. This study exemplifies how technology can accelerate drug discovery by breathing new life into shelved medicines that have already been tested for other diseases.

“In this study, we were able to culture large numbers of adult brain cells, providing a powerful new tool for finding treatments for neurological disorders,” said Mark H. Tuszynski, M.D., Ph.D., professor in the Department of Neuroscience at the University of California, San Diego, and lead author of the study. “These are not stem cells, but adult brain cells that have not previously been cultureable. The ability to culture adult brain cells could help test new drugs and gene therapies for many brain diseases.”

Van Niekerk said advancing Tiorphan into clinical trials is an important next step. “We are currently working to optimize thiorphan for future clinical trials, a task made easier by the fact that this drug is already safely used in humans.”

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