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Doloromics is a precision neuropharmaceuticals company. It was set up four years ago, to use newer technologies, particularly in the omics space, to take advantage of different single-cell transcriptomic technologies or proteomic technologies to better understand the progression of neurological diseases like chronic pain.
The Doloromics pipeline is built upon a proprietary discovery and validation platform DOLOReS.
Jackson Brougher, chief scientific officer and co-founder of Doloromics, is our guest on this week’s Beyond Biotech podcast.
Brougher stressed the importance of Doloromics building databases to identify novel therapeutic targets.
“Once we had done that, the second stage of our evolution was to build a computational platform to identify novel therapeutic targets from the data that we were generating,” he noted.
“From there, we entered this build phase that we’ve been in for the last few years of actually starting to build out a therapeutic pipeline with several different assets in it.
“We haven’t listed what those targets are just yet, but we’ve listed some of the indication spaces that we plan to go after, things that are being addressed in the field right now, like migraine, but also looking at some underserved areas like fibromyalgia.”
Table of contents
Understanding pain: definitions and prevalence
The International Association for the Study of Pain defines pain as an unpleasant sensory and emotional experience related to, or associated with, actual or potential tissue damage.
Brougher said pain is what we perceive that can be related to tissue damage or disease but isn’t necessarily. Chronic pain, he continued, is then defined as pain that persists or recurs for more than three months.
He added that the US has experienced a opioid epidemic, which is partly fueled by the incidence rate of chronic pain.
“Commonly the percentages that you’ll see really range anywhere from 20 to 30% of the population worldwide. So, it’s a significant proportion of the human population that suffers from chronic pain,” Brougher said.
“I think one of the things that’s really notable here is that that increases with age. So, while that may be 20 to 30% of the total population, when we look at elderly populations or individuals over the age of 65 in particular, you start to see that prevalence exceeding 50% of the population. This has huge downstream costs both economically and personally.”
How subjective is pain?
The presence of certain diseases and conditions is clear, but just how subjective is pain?
“Pain is an individualized experience,” Brougher stated.
“To an extent, we are all familiar with going to the doctor and pointing at a series of faces from zero to 10, with zero being a smiley face and 10 being a very upset face. But pain is a uniquely individual experience. When we’re relating that experience to others, you do run the risk of it being minimalized.”
Doloromics’ approach: delineating the idea of nociception versus pain
He continued that Doloromics is delineating the idea of nociception versus pain itself.
Nociception is the central nervous system (CNS) and peripheral nervous system (PNS) processing noxious stimuli. When nociceptors and their pathways are activated, pain is the subjective experience felt as a result.
“If we remove a signal, we are able to stop the pain, in this case migraine. I think that’s just a remarkable advance for the field at this point.”
“When we at Doloromics think about nociception, we primarily focus on nociceptors, which are highly specialized sensory neurons within the peripheral nervous system. But kind of backing up a step, nociception itself is referring to physiological processes, our body’s ability to detect harmful stimuli, again, originating in the periphery and signaling to higher central brain areas.
“So, the first step of nociception is the activation of those sensory neurons, those nociceptors, in response to either tissue damage or other stimuli, thinking back to like a neuro 101 course, those can be broadly grouped into thermal, mechanical, or chemical stimuli that are causing those nociceptors to activate.”
Brougher explained that nociception itself has been thought of as four key processes, beginning with transduction.
Transmission follows from the periphery to the spinal cord to higher brain regions. The final two processes are modulation of that signal within the spinal cord, and then perception.
Brougher said: “I believe that recent clinical successes in addressing that actual transmission of the signal, both the transmission of the signal and the transduction of the signal, really do pave the way for us as a precision neuropharmaceutical company to come in and develop novel therapeutics.”
The rise of sodium and ion channels
The biggest challenge in developing new treatments for chronic pain has been identifying targets, Brougher said.
“In the field right now, the hot areas of this next stage of analgesics is largely around sodium channels and other ion channels as well.”
Brougher said since the beginning of 2024 three companies have been notable in their work in the area.
Vertex Pharmaceuticals has VX-548, a clinical stage NAV1.8 channel inhibitor. Latigo Biotherapeutics Inc. is also developing sodium channel inhibitors, and Nocion Therapeutics is developing ion channel inhibitors.
“What they have in common is that they are specifically looking to modulate that initial transduction or transmission of those painful signals from the periphery to the brain,” Brougher said.
CGRPs for chronic pain
Brougher also addressed the CGRP (calcitonin gene-related peptide) field.
“There’s a number of players in the CGRP field now, both monoclonal antibodies, and also several small molecule inhibitors for the receptor itself that are clinically approved now.
“I think these really encapsulate our approach at Doloromics a little bit better than the NAP channel approaches that others are taking.”
He said CGRP is a neuropeptide that, when released from neurons, causes a potent vasodilation, including in migraines.
“In these patients who have previously had treatment-resistant migraines, the CGRP antibodies are remarkably successful in being used as a preventative measure. When we think about migraine and migraine treatments, we can think about treatments as either being preventative, or abortive.
“The CGRP antibodies are typically preventative. They’re not going to be able to resolve a migraine once it’s actually set in in a patient. That said, these kind of paved the way for developing a precision medicine approach to treating different types of pain like migraine. If we remove a signal, we are able to stop the pain, in this case migraine. I think that’s just a remarkable advance for the field at this point,” Brougher said.
Advances in omics technologies for chronic pain
“What we’re able to do now, particularly with technology such as single cell transcriptomics, is to take every cell in a given tissue and fully understand its molecular landscape,” Brougher explained.
“This allows us not just to look and see whether a drug target is expressed in a given tissue or not, but to actually understand better how these cellular populations differentiate from one another and how they may then be differentially affected by different types of disease.
“In the role of what we’re interested in, sensory neurons, nociceptors, we’re able to take human dorsal root ganglion and then using these advances in omics technologies, take the tissue, dissociate it, sequence it, and then categorize and characterize all the different populations of nociceptors.”
Brougher said this is important because different populations of nociceptors play different roles in our perception of the world around us.
“Nociceptors are not a generic one-size-fits-all class of neuron where they’re all conveying the same information about the world around us. You have nociceptors that convey things like temperature, nociceptors that convey mechanical responses, and you have nociceptors that can convey things like chemical responses.”
Doloromics’ DOLOReS platform
Doloromics’ DOLOReS platform has an in silico and an in vitro or ex vivo portion.
“The in silico portion of the platform is taking human tissue, primarily dorsal root ganglion or spinal cord. In addition, we’re obtaining tissue from synovium from patients with various types of arthritis. We also look at things like other peripheral nerves.
“We take all of these tissues and we profile them omically, using bulk transcriptomics to single-cell transcriptomics to proteomics, and even looking at things like the epigenome through spatial attack sequencing or looking at microRNA regulation networks. And, in doing so, what we do is develop this comprehensive atlas, or what we call nociceptive cartography, around the tissue and how our sensory tissue changes across various different types of disease.
“From there, we take a fairly involved computational approach to identify the signals between cells and within cells that are changing and leading to the nociceptors becoming hyper excitable, which is the key part or basis of the platform itself. We’re trying to understand better what signals are not just changing, but what signals are leading to the increase in excitability, which leads to the increase in transmission from the periphery to the central nervous system.
“From there, we identify a short list of therapeutic targets that we want to validate in our wet lab.”
Brougher continued: “What we’re doing is we’re taking traditional neuroscience approaches like running various different electrophysiological assays, say plating cells on a microelectrode array, which allows us to monitor the cells firing rate. The cells’ potential firing rate relates to their state of excitability.
“What we may see when we culture, say, human tissue on a microelectrode array is that at a steady state or baseline, it’s fairly silent or not firing very often. However, when we add a given factor that our platform has identified, we see that the signals increase, say, in response to a growth factor that DOLOReS has nominated as being a key driver of chronic pain. We add that exogenous growth factor to the cell’s microenvironment, and we see that the nociceptors or the sensory neurons increase their firing rate. From there, what we can do is monitor how long that pain phenotype persists and how it changes the underlying baseline of the tissue that we’re working with. From there, we can take that next step of beginning to develop therapeutics, which we can then again test in that same test system.”
Next steps for Doloromics
Brougher said the company’s lead asset is approaching IND (investigational new drug application).
“We’ll focus on developing our therapeutics, likely up to a stage where we can then partner them with larger pharmaceutical companies. We really believe our expertise is in identifying novel therapeutic targets. I don’t see us ever really going into those late-stage clinical trials, things like phase three clinical trials.
“I think we have a lot more strength in developing the earlier stages and then partnering for later stages.”
To learn more about this topic
Here are some links to more articles on the subject of new pain treatments.
- Gene therapy opens new possibilities for treating chronic pain (University of Oxford)
