New Research From UT Could One Day Treat Chronic Pain Without Opioids

By Ava Motes in 40 Acres, May | June 2024, Research on April 30, 2024 at 7:44 pm | No Comments

Three decades ago, if you had asked Dr. Stephen Martin how the molecules he synthesizes would be used today, he might have given you any number of answers ranging from cancer to Alzheimer’s research. He says it’s really a matter of “serendipity” that his life’s work may now culminate in a breakthrough non-opioid treatment for chronic pain.

“A lot of people start off some research project, and they say, for example, ‘pain is a serious problem. I want to develop a treatment,’” Martin says. “The way we got into this is completely different.”  

Martin is part of a team of researchers from UT Austin, the University of Texas at Dallas, and the University of Miami who recently identified a molecule that effectively reduced symptoms of neuropathic pain in mice trials. The molecule, dubbed FEM-1689, works by targeting a previously under-researched protein and could soon be integral for treating neuropathic pain without the side effects and addictive potential of opioids.  

Although Martin now finds himself on the cutting edge of new mechanisms for reducing neuropathic pain, he says this work began, in a way, as a shot in the dark—made lucky by a few open-minded biologists and a hunch towards the road less taken.   

Martin is currently a chemistry professor and head of the Martin Research Group at UT, focusing on chemical synthesis—or “molecule making,” as he calls it. But the seeds for his current research were planted some 35 years ago, when Martin was working for a program funded by the National Institutes of Health. There, he conceptualized an approach to develop hundreds of biologically active chemicals and determine their potential applications for human health.  

“We didn’t have any idea what we’re looking for, but we screened the molecules against a bunch of targets, and we came across this one group of molecules that bound to these things called sigma receptors,” Martin says.  

Though Martin did not know it at the time, he would later uncover the important role that sigma receptors play in regulating the integrated stress response—a network of cellular signaling that is activated in response to diseases and injuries. Joining him in this research was Dr. Jim Sahn, a co-author on the latest paper who began synthesizing and refining molecules with Martin as a postdoctoral researcher in 2009. Together, they learned there are two types of sigma receptors: sigma-1, a protein known to have neurological effects, and sigma-2, which was minimally studied.   

“Lots of times, you know exactly what a protein is,” Martin says. “But the sequence of this particular sigma-2 protein wasn’t known. It was just a pharmacological binding site.”  

Martin says he and Sahn hypothesized that sigma-2 might have neurological applications, in part because no one else had ever considered it. They went on to identify the protein as TMEM97, but to understand its effects, they needed to find biologists willing to take a risk and help test their compounds.  

Martin first partnered with researchers at Stanford and the Bascom Palmer Eye Institute and found that TMEM97 may help slow the effects of Alzheimer’s and retinal degeneration. But the biggest breakthrough came in 2014 when Martin was first introduced to Dr. Theodore Price, one of the foremost researchers in the field of neuropathic pain who would go on to run the Price Lab at UT Dallas. There, he tested Martin and Sahn’s chemicals as part of his research into new treatments for neuropathic pain.

“Neuropathic pain is a really big clinical problem, and the existing drugs don’t work very well at all for most people,” Price says. “So I’ve always been looking for opportunities to work with medicinal chemists that have the capability of making molecules that can actually progress.”  

In 2017, the researchers co-founded NuvoNuro, Inc., a company devoted to developing new therapeutic drugs using these synthetic molecular compounds. They’ve since tested Martin and Sahn’s chemicals against various causes of neuropathy including diabetes, chemotherapy, and nerve damage.  

The team’s latest study involved administering FEM-1689 (a compound named after Martin’s wife’s initials) to target TMEM97 in mice suffering from sciatica. They found that the compound effectively reduced hypersensitivity, allowing the mice to place more weight on their nerve-damaged paws than before. The research also isolated the mechanistic underpinning of this response.  

“The really important thing in this paper is that we figured out that it really is a specific action of these drugs on TMEM97,” Price says. This is important because it shows that compounds like FEM-1689 can target TMEM97 in isolation without engaging opioid receptors.  

The current research is being funded by a nearly $7 million grant from the National Institutes of Health HEAL (Helping to End Addiction Long-term) Initiative, which supports finding scientific solutions to the national opioid crisis. Although targeting TMEM97 has several other potential therapeutic uses, advancing non-opioid pain treatments is a top priority.

In 2020, the CDC estimated that 1.6 million Americans suffered from opioid use disorder, and more than 70,000 people died of drug overdoses that year. Sahn says this research is particularly exciting because it could provide a new and safer path to pain relief with less potential for misuse.  

“We are now a year into the HEAL grant with a goal of developing a drug candidate that is ready to advance to clinical trials, which obviously will get us a step closer to helping the millions of people that are currently not being served by available pain meds,” Sahn says.  

After the paper’s publication in November 2023, numerous chronic pain patients contacted Martin to ask when the compound might make its way to pharmacy shelves. He understands their urgency, especially since he previously experienced severe prolonged leg pain, but he says clinical trials are still a few years away.  

The researchers are currently working to refine the compound, minimizing potential side effects and ensuring long-term efficacy for those who might rely on it as a daily pain medication. Although this is a lengthy process, the researchers are confident in its success.  

“We think by the end of this grant, which has about four years left on it, we’ll have a candidate that’s ready to enter phase one clinical trials,” Sahn says. “I’m feeling very optimistic. That paper was based on discoveries and efforts that started [years] ago, so it’s great to see our research taking us in a path that will hopefully affect many people in a positive way.” 

CREDIT: Illustration by Maddie Chiang

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