Unlocking the door to a complex sense

The Nobel Laureates in Medicine 2021 revealed the mechanisms that underpin the different sensations of temperature and touch. Their discoveries have led to a better understanding of how the nervous system codes sensory information, as well as triggering a myriad of exciting new questions.

Since the 1940s, it has been demonstrated that nerve cells are highly specialized for detecting and transducing differing types of stimuli, allowing a nuanced perception of our surroundings, stated the Nobel Assembly at Karolinska Institutet at the Prize announcement. However, how temperature and mechanical stimuli are converted into electrical impulses in the nervous system was until the 1990s unknown. The Nobel Laureates in Physiology or Medicine 2021 discovered that receptors (i.e., sensors) are able to detect and convert heat and touch into impulses, and identified which receptors are the main players. These findings have led to a rapid increase in our understanding of how the nervous system senses heat, cold and mechanical stimuli.

“You could say that this year’s Laureates unlocked one of nature’s secrets.”

“These receptors translate our surroundings into something we can perceive and adapt to. This is incredibly important, for example for everyday things like lifting a glass of water to your mouth or walking, but also when we reflexively snatch our hand away from a hot stove. You could say that this year’s Laureates unlocked one of nature’s secrets,” said Patrik Ernfors, Professor and member of the Nobel Committee at Karolinska Institutet after the Prize announcement.

A chili pepper and a new receptor

In the late 1990s David Julius, working at the University of California in San Francisco, became interested in the chemical compound capsaicin, an active component of chili peppers, which are plants belonging to the genus Capsicum. He wanted to understand how capsaicin causes the burning sensation we feel from chili peppers. It was already known that capsaicin activated nerve cells that caused pain sensation but exactly how this worked was not known.

David Julius. Photo: University of California, San Francisco, PNAS

Together with his colleagues he created a library consisting of millions of DNA fragments that corresponded to genes that are expressed in the sensory neurons, which can react to pain, heat, and touch. By searching this library in the lab (they expressing individual genes in cultured cells that normally do not react to capsaicin), they were hoping to find a DNA fragment encoding the specific protein that was capable of reacting to capsaicin. Luckily, they were able to identify the one gene for capsaicin sensing. They also showed that this gene encoded a new ion channel protein, a capsaicin receptor, which was later named TRPV1. When they investigated TRPV1’s ability to respond to heat, Julius realized that he had discovered “a heat-sensing receptor that is activated at temperatures perceived as painful,” describes the Nobel Assembly at Karolinska Institutet. His finding of TRPV1 was published in 1997.

Trpv1 Pip2 bilayer. Created using PyMol and a homology model of the TRPV1 ion channel based on a homology model published in Brauchi et al. (June 2007). PNAS 104

Capsaicin had thus been the right tool for understanding painful heat. If you have ever eaten (or accidentally eaten) a hot chili pepper, perhaps you remember that what you feel afterwards is not only uncomfortable, but even painful. Many of us would also start sweating, indicating that capsaicin tricks the brain into thinking that there is a temperature change.

Julius’ findings led to many more findings, and additional temperature-sensing receptors have been identified since TRPV1. For example, both Julius and his co-Laureate, Ardem Patapoutian, were able to identify a receptor that activated cold, TRPM8.

New mechanosensitive ion channels

Besides activation of cold, Ardem Patapoutian, working at the Scripps Research Institute in La Jolla, also set out to understand more about how mechanical stimuli could be converted into our senses of touch and pressure. Together with collaborators, he identified a cell line that gave off an electrical signal when individual cells were poked with a micropipette (i.e., pressure-sensitive cells). He assumed that the receptor activated by mechanical force was an ion channel, and 72 candidate genes encoding possible receptors were identified. These genes were inactivated one by one in order to find the gene responsible for mechanosensitivity. Patapoutian was able to identify the gene and a new mechanosensitive ion channel had been discovered.

Ardem Patapoutian. Photo: Scripps Research Institute

The choice of model system was crucial for his success, said Patrik Ernfors in a news release from Karolinska Institutet. “He understood that we would never find how touch translates into electrical impulses if you don’t have a simple model system. Another key was that he understood that he had to look for genes with certain properties, which made them probable as receptors, but it was still an incredibly arduous job,” he said.

“He understood that we would never find how touch translates into electrical impulses if you don’t have a simple model system. Another key was that he understood that he had to look for genes with certain properties, which made them probable as receptors, but it was still an incredibly arduous job.”

The new ion channel was named Piezo1, after the Greek word for pressure and Patapoutian’s findings were published in 2010. A second gene, similar to Piezo1, was also discovered, and named Piezo2. Further studies established that these two ion channels are directly activated by the exertion of pressure on cell membranes. Subsequent studies showed that Piezo2 is essential for the sense of touch and was also shown to play an important role in proprioception i.e., the sensing of body position and motion. “This means your sense of where your limbs are compared to your body. Most people don’t even think about that being an important sense. Without it you cannot walk, you cannot stand up, and so it’s a very important part of physiology,” described Patapoutian in a Nobel Media interview just after the Prize announcement.

PIEZO channel. Photo: Scripps Research

Touch – so many modalities to it

In his Nobel lecture “How do you feel? The molecules that sense touch”, Patapoutian described how seeking the answer to one fundamental question led him to a very complicated sense and many new questions.

“If you really start digging deep into touch, it’s so different than the rest of the senses. There’s so many modalities to it. There’s different physical forces we sense, like temperature and mechanical force. There’s itch. There’s this spectrum of pleasant touch to noxious to painful,” he said in an interview with Brian Resnick, Vox, October 6 2021. “If you put on top of that proprioception and internal organ sensation, it’s a very complicated sense that we don’t really understand. There’s no totally, well-agreed terminology even to describe clearly what we mean by touch and somatosensation.”

Somatosensation is often described as the sense at the center of the ability to feel our body surface and internal organs. Somatosensation includes touch (mechanical and thermal), pain (mechanical, thermal and chemical), and proprioception (sense of self, the location and movement of our body).

New findings and new questions

The discoveries of pressure- and temperature-sensitive ion channels have led to major research area advances. Today, we have a better understanding of how heat, cold and mechanical force can initiate the nerve impulses that allow us to perceive and adapt to the world around us. The discoveries have also led to many new questions and ongoing research is focusing on clarifying further the receptors’ functions in different physiological processes.

“For example, we have found that red blood cells can sense pressure and adjust their volume. Also, in clinical settings when you have too much of this sense you can actually have dehydrated red blood cells that are protective against malaria. We also have found that in immune cells this protein regulates things like how much iron there is in your blood. Nobody ever could have thought that pressure sensing is related to these processes,” said Patapoutian in the Nobel Media interview.

Piezo1 and Piezo2 channels have also been shown to regulate respiration and urinary bladder control. They may also be involved in tracking how much the stomach stretches during a meal, and how much food passes through the intestines during digestion, described Patapoutian in his Nobel lecture.

TRPV1 and Piezo2 have also both been found to be important when it comes to chronic pain, and are explored as new targets for drug development.

The seminal discoveries by the 2021 Nobel Laureates have explained how heat, cold and touch can initiate signals in ur nervous system. The identified ion channels are important for many physiological processes and disease conditions. Illustration: Mattias Karlén/The Nobel Committee for Physiology and Medicine

Targeting neuropathic pain

A company who’s approach captures the fundamental Nobel discoveries is Swedish AlzeCure Pharma, founded in 2012. “The Nobel Prize has led to our company and our pain project getting a lot of attention. For example, we have received several inquiries about our neuropathic pain project from other pharma companies looking to in-license promising pain projects in areas of great medical need,” says Martin Jönsson, CEO, AlzeCure Pharma.

“TRPV1 has been shown to be up-regulated on neurons, to have reduced stimulation thresholds, and to cause an increased perception of pain. It has also been shown to be up-regulated in the skin of individuals with certain types of neuropathic pain.”

The company’s drug candidate for neuropathic pain, ACD440, is based on the discoveries of the TRPV1 receptor. TRPV1 has been shown to be up-regulated on neurons, to have reduced stimulation thresholds, and to cause an increased perception of pain. It has also been shown to be up-regulated in the skin of individuals with certain types of neuropathic pain. So, blocking the TRPV1 receptor would therefore be interesting when developing new analgesics (painkillers).

“There are currently no TRPV1 antagonists [substance that can temporarily block TRPV1] on the market so ACD440 could be a so-called first-in-class,” says Jönsson. “In addition, we are developing a gel for local treatment of peripheral neuropathic pain in order to both be able to provide a good effect and also to avoid systemic side effects.”

Martin Jönsson, CEO, AlzeCure Pharma, and colleagues. Photo: Jenny Larerqvist

Neuropathic pain is primarily a chronic disease caused by dysfunction or an injury to the sensory nervous system. Patients could suffer from diabetic neuropathy, or a consequence of shingles, or nerve injury from an accident or surgery.

“Nearly 80% of all patients suffering from neuropathic pain are not satisfied with their current treatment, and there are more than 600 million people living with neuropathic pain,” says Jönsson. “In addition, more than 60% of neuropathic pain patients in the USA have been prescribed opioids, which is problematic and something that healthcare and authorities want to avoid in order to overcome the existing opioid crisis in the country. So there is a great need for more effective and safer treatments.”

Using opioids, i.e., substances that act on opioid receptors to produce morphine-like effects, means a significant risk of withdrawal symptoms and dependency. Each year 69,000 people worldwide die of opioid overdose, and 15 million people have an opioid addiction (Parthvi et al., American Journal of Therapeutics, 2019.

Martin Jönsson, CEO, AlzeCure Pharma. Photo: Jenny Lagerqvist

In December 2020, AlzeCure initiated a phase Ib clinical trial for ACD440 to assess tolerability, safety and early signals of efficacy.

“We are planning to initiate our next clinical study, a phase II study, against peripheral neuropathic pain and to actively work towards an out-licensing of the project,” says Martin Jönsson.

“Moreover we are seeking to be able to conclude and report results for NeuroRestore ACD856, which has a focus on Alzheimer’s disease, as well as initiating the project’s next clinical study. We are also continuing the development of our second Alzheimer’s project, Alzstatin, as well as our TrkA-NAM project against knee-joint arthritis and other difficult pain conditions. So, I can really say that we are quite busy after completing a successful 2021.”

Tackling the diabetes pandemic

At Swedish company Pila Pharma, the TRPV1 receptor, or as they call it, the chili-receptor is used as the leading principle for a novel treatment of diabetes.

“The Nobel Prize has given me the opportunity to share how important I think and believe TRPV1 is. In addition I have for the first time had a reason to share how grateful I am that Julius made his discovery, published his results and made his TRPV1 knock-out mice model [TRPV1 is inactivated] available to others,” says Dorte X. Gram, CEO and founder of PILA Pharma.

Dorte X. Gram, CEO and founder, Pila Pharma. Photo: Peter Brinch

While working at Novo Nordisk, before founding PILA in 2014, Dorte used these knock-out mice and was able to show that, after having a high-fat diet, the mice did not become insulin resistant. These mice had better insulin secretion than normal mice fed the same diet. “This data was part of my patent application on TRPV1 inhibitors as a mode of action to treat diabetes,

“Inhibition of the activity of the capsaicin receptor in the treatment of obesity and obesity-related diseases and disorders” which includes diabetes, and later became the platform on which Pila Pharma was built,” she describes.

Her company is today developing a TRPV1 antagonist, XEN-D0501, as a novel type of oral anti-diabetic agent.

“Our tablet works through a completely new target within diabetes, TRPV1, which is known to have effect on the experience of pain and inflammation regulation.”

“Our tablet works through a completely new target within diabetes, TRPV1, which is known to have effect on the experience of pain and inflammation regulation,” says Dorte X. Gram. “I believe that diabetes type 2 is an inflammatory disease and by treating “root-cause” I think that we will achieve a better effect, not only when it comes to glucose regulation but also, as the scientific literature indicates, we may see a positive effect on the secondary diseases of diabetes. For example, on cardiovascular diseases, which cause people with diabetes type 2 to die ten years prematurely. Imagine being able to prevent that. That would be cool and obviously very meaningful!”

XEN-D0501 is a synthetic small molecule that was in-licensed in 2016. Prior to in-licensing, it had been found to have a good safety profile in other (non-diabetic) patient groups.

“The tablet is very small and simple to swallow. Another advantage is that it is relatively cheap to produce, which means that it may be possible to price it quite low, so a lot of diabetics can afford it. This is very important to me because my goal is to help to treat this growing group of diabetics who are currently not receiving adequate treatment,” says Dorte X. Gram.
In the eight phase I and II clinical studies that have been performed so far there have not been many side effects and in the two diabetes studies the company themselves have performed, no serious side effects have been registered. “In our most recent study, which was a pilot phase II study, we were also able to show that patients who received XEN-D01501 for one month had a statistically significant better insulin secretion than other patients with diabetes type 2 who received placebo treatment,” says Dorte.

Dorte X. Gram. Photo: Peter Brinch

Diabetes has increased fourfold over the past 25 years, and according to the WHO, it is a worldwide pandemic. Approximately 90% of all diabetics suffer from type 2 diabetes, whilst approximately 10% suffer from type 1 diabetes.

Last summer Pila Pharma was listed on Nasdaq First North GM in Stockholm with the goal to finance the road ahead towards phase IIb data, where they aim to demonstrate that XEN-D0501 has a good effect on blood sugar regulation after three months treatment without contemporary unacceptable side effects.

“First, we aim to perform a three month-long preclinical safety assessment study in animals, and then, in about a year, move on to three month tests in humans. Phase IIb is our first great big interim goal, which might trigger a collaboration with a larger pharma company regarding the development through phase III and registration and marketing globally. The ultimate goal is to help treat the over 500 million people suffering from diabetes. They and their families will suffer a sad fate if the disease is not treated. There are long lead times within drug development, but slowly but surely we will reach our goal!” concludes Dorte X. Gram.