The quest for effective and safe solutions for weight loss is one of the greatest challenges of modern medicine. In an era where the global obesity rate is reaching pandemic proportions, the pharmaceutical industry is offering increasingly sophisticated drugs. Among them, drugs from the class of GLP-1 receptor agonists, such as the popular Ozempic or Zepbound, stand out, having shown significant results in reducing body weight and controlling diabetes. However, their success is often overshadowed by pronounced side effects that drastically reduce the quality of life for patients and lead to the discontinuation of therapy. This is precisely what has prompted scientists to search for alternative pathways that could offer the "holy grail" – weight loss without nausea.

The problem with existing therapies is fundamental. Although they are extremely effective in suppressing appetite by acting on centers in the brain, GLP-1 drugs bring with them the burden of unpleasant gastrointestinal disturbances. The statistics are relentless: as many as 70% of patients discontinue therapy within the first year precisely because of the intense nausea and vomiting these drugs cause. Such a scenario makes long-term maintenance of the achieved weight almost impossible, turning a potential solution into a temporary measure with a high price. In this context, a team of medicinal chemists from Syracuse University, led by Professor Robert Doyle, has discovered a potentially revolutionary approach that could change the rules of the game.

A New Approach: Targeting Supporting Cells Instead of Neurons

Traditionally, neuroscience research and drug development have focused on neurons as the primary targets in the brain. Neurons are the fundamental units of the nervous system, responsible for transmitting signals, so they logically emerge as a target for modulating functions like appetite. Drugs from the GLP-1 class work exactly this way – they target neurons in the back of the brain (brainstem), an area crucial for controlling hunger and satiety. However, this same region is also responsible for the sensation of nausea, which explains why side effects are so common and pronounced.

Professor Doyle and his multidisciplinary team decided to think outside the box. They asked themselves a key question: what if neurons are not the only players in this complex game? What if the "supporting" cells that surround neurons have their own, hitherto neglected role in appetite regulation? The focus of the research was shifted to glial cells, and particularly to astrocytes, which have long been considered merely passive support for the neural network.

“We wanted to explore the possibility that supporting cells produce their own peptides or signaling molecules that could be key in the process of weight loss,” said Doyle, who is a professor of chemistry at the College of Arts and Sciences at Syracuse University and a professor of pharmacology and medicine at SUNY Upstate Medical University.

The Role of Astrocytes: More Than Just Support

Astrocytes, star-shaped cells that make up a significant portion of the brain's mass, are far from passive observers. They actively participate in maintaining brain homeostasis, regulate synaptic activity, contribute to the blood-brain barrier, and, as is now being shown, communicate via their own chemical signals. Collaborative research involving scientists from the University of Pennsylvania and the University of Kentucky revealed that these very cells play an active role in reducing the feeling of hunger, although this mechanism has not been studied in detail until now.

Professor Doyle uses a simple but powerful analogy to explain this concept. "Imagine every neuron in the brain as a light bulb," he explains. "The neurons themselves are the most obvious target, but for the light bulb to shine, it needs all the other parts: the wiring, the switch, and even the filament. It is these 'supporting' components, which allow the bulb to shine, that represent our new focus."

From ODN to TDN: The Path to a Drug Without Side Effects

The research team managed to identify a specific molecule naturally produced by astrocytes in the back of the brain – octadecaneuropeptide, abbreviated as ODN. Laboratory tests showed that direct injection of ODN into the brains of rats leads to significant appetite suppression, a consequent loss of body weight, and, very importantly, improved glucose processing. This was proof that they were on the right track.

However, injecting a drug directly into the brain is not a practical or applicable method of treatment for humans. Therefore, the next step was to create a modified, more stable, and more effective version of this molecule that could be administered via standard injections, similar to how Ozempic or Zepbound are administered today. Thus, tridecaneuropeptide, or TDN, was created. This new molecule was designed to be able to cross the blood-brain barrier and act specifically on supporting cells, without directly activating the neural pathways that cause nausea.

Promising Results in Animal Models

The efficacy and safety of the new molecule TDN were tested in obese mice and, particularly significantly, in musk shrews. Musk shrews were chosen as a key animal model because, unlike mice and rats, they have a vomiting reflex very similar to humans. This makes them ideal candidates for testing side effects like nausea.

The results were extremely encouraging. Animals treated with TDN not only lost weight and showed a better insulin response, but, most importantly, they showed no signs of nausea or vomiting. They achieved a therapeutic effect without the unpleasant side effects that are a stumbling block for GLP-1 drugs. This discovery confirmed the hypothesis that by targeting astrocytes, the mechanism that causes nausea can be bypassed.

"A Shortcut in a Marathon": How TDN Bypasses the Problem

One of the main goals of the research team was to achieve weight loss without targeting new therapeutic molecules to neurons. Professor Doyle describes this approach as a "shortcut in a marathon."

"Instead of running the entire marathon from the very beginning, as current drugs do, our approach of targeting downstream pathways in supporting cells is like starting the race halfway through. This reduces the unpleasant side effects that many people experience," says Doyle. "If we could directly hit that downstream process, we might not have to use GLP-1 drugs with their side effects. Or we could reduce their dosage, improving the tolerability of these drugs. We could more directly trigger the weight loss signals that occur later in the signaling pathway."

In other words, while GLP-1 drugs trigger a long cascade of chemical reactions that ultimately leads to reduced appetite but also to nausea, TDN skips the initial steps and acts directly on the appetite suppression mechanism within the supporting cells. It is an elegant solution that targets the core of the problem, not its symptoms.

The Future of Treatment: CoronationBio and Clinical Trials

To translate this revolutionary discovery from the laboratory into the real world and clinical practice, a new company called CoronationBio has been launched. The company has licensed the intellectual property related to ODN derivatives for the treatment of obesity and cardiometabolic diseases from Syracuse University and the University of Pennsylvania. The main goal of CoronationBio is to translate promising preclinical candidates into drugs ready for clinical trials in humans.

They are currently partnering with other pharmaceutical companies to accelerate development and optimize production. According to optimistic but realistic estimates, the first clinical trials in humans could begin in 2026 or 2027. If the results from animal models are confirmed in humans, it could mark the beginning of a new era in the treatment of obesity – an era in which patients no longer have to choose between efficacy and quality of life.

This research not only offers hope for the development of a new class of drugs but also deepens our understanding of the complex mechanisms that govern appetite and metabolism. The shift in focus from neurons to astrocytes opens up a whole new field of research and potential therapeutic targets, not only for obesity but also for other neurological and metabolic disorders.

Source: Syracuse University