November 5, 2026 | Development of next-generation drugs for treating systemic inflammation and cognitive impairment is ready to begin, backed by a study linking abnormalities in the cerebellum and frontal lobe regions of the brain in pulmonary hypertension patients to the same processes driving the disease in their lungs and heart. The emerging therapeutic target and biological marker is known as nuclear receptor coactivator 7 (NCOA7), which could prove useful in the management of not only cardiopulmonary conditions but also neurodegenerative and autoimmune diseases—"anywhere that inflammation is raging out of control,” according to Stephen Chan, M.D., Ph.D., director of the Vascular Medicine Institute and Center for Pulmonary Vascular Biology and Medicine at the Pitt School of Medicine and the University of Pittsburgh Medical Center.
As a cardiologist, Chan’s focus is on pulmonary hypertension, historically defined by high blood pressure in the pulmonary arteries that carry blood from the right side of the heart to the lungs. But as a scientist and founder of startup Amlysion Therapeutics, his interests extend more broadly to the molecular and metabolic drivers of pulmonary vascular disease, the interaction and crosstalk between multiple biological processes fueling the disease cascade and translating mathematical disease models and metabolic targets into novel therapeutic interventions.
Chan says he has been inherently interested in how organ systems communicate with one another for more than a decade, and those answers are seemingly now on the horizon. This should be especially well appreciated by patients with pulmonary hypertension, given that the “brain fog” they’ve been reporting for years has been largely ignored by physicians. This is because, beyond the heart and lungs, the rest of the body wasn’t prioritized, he says.
It wasn’t until recently that Chan had enough resources and expertise to begin challenging that assumption, which he describes as a “high-risk, high reward situation.” If results from the recently published study are any clue, the gamble could pay off.
Findings identify NCOA7-linked inflammatory dysfunction in the brain and provide targets for detecting, treating, and predicting the likely future course of pulmonary hypertension (Journal of Clinical Investigation, DOI: 10.1172/JCI195110). The research demonstrates that a genetic variant in the NCOA7 gene triggers both lung pathology and neuroinflammation, leading to consistent and measurable brain tissue loss.
It also supports modern medical thinking that human disease doesn’t reside within a single compartment or tissue, he says. “It’s really quite syndromic.” The many different disease manifestations seen with pulmonary hypertension notably include cognitive dysfunction, memory loss, and impaired executive function.
Physicians have traditionally had “hand-waving explanations” for the cognitive symptoms being reported by pulmonary hypertension patients, such as low blood oxygen levels or mood disorders like anxiety and depression. The reality, says Chan, is that many patients who don’t have any of those ancillary health conditions still can suffer from cognitive decline.
Supporting evidence comes from multiple research centers in and outside the United States, including a large study in China suggesting that over 50% of patients experience some sort of cognitive impairment (American Journal of Respiratory and Critical Care Medicine, DOI: 10.1164/rccm.202204-0726LE). That did not, until recently, have a reasonable mechanistic explanation, Chan notes.
In a study in nearly 3,000 pulmonary hypertension patients published last year, Chan and his team discovered that the disease is associated with dysfunctional lysosomes that worsen survival odds (Science, DOI: 10.1126/science.adn7277). The culprit of the proinflammatory dysfunction was also identified: deficiency of NCOA7.
The latest study further upends thinking about pulmonary hypertension, and cardiopulmonary disease in general, he adds. The hope is that physicians in the field will think more about how best to get the information they need to better manage patients, and “perhaps even push the envelope further” for molecularly targeted medical treatments that impact brain function.
The exciting possibilities include identifying behavioral and lifestyle modifications as well as drugs and therapies that improve cerebellar or frontal lobe activity to improve the way pulmonary hypertension progresses, says Chan. Broadened understanding that inflammation is the communication bridge between the body and the brain might also help explain why vascular disease occurring earlier in life heralds an increased risk of developing dementia and neurodegenerative disease later in life.
Pulmonary hypertension is an umbrella term referring to five main groups of patients, based on the underlying cause of high blood pressure in the lungs, Chan explains. Probably millions of people in the world have the disease, but all the targeted therapies currently utilized to treat it are focused on pulmonary arterial hypertension that accounts for only about 3% of the affected global population. “In that regard, there’s a huge unmet need in this space.”
Data generated by Chan and his team thus far suggest that many different types of pulmonary hypertension patients suffer from the same type of cognitive and brain abnormalities, and not just the small sliver with pulmonary arterial hypertension. These include so-called “group 2” patients whose disease is due to left-sided heart disease and “group 3” patients with chronic lung conditions.
Interestingly, the same pattern of brain abnormalities seen across patients with pulmonary hypertension were not found on brain scans of patients with other types of heart and lung diseases, or even psychiatric diseases, he continues. “The cerebellar and frontal lobe connection is really specific to pulmonary hypertension,” a surprising finding that awaits explanation.
Patient management is bound to change, with pulmonologists and cardiologists taking on more generalist roles, says Chan. Doctors treating pulmonary hypertension are “going to need to understand what’s happening in the neurologic space, in the psychiatric space, perhaps even other organ systems that are being affected by this inflammation program that we’ve been studying—it could be the kidneys ... [or] the liver.”
The change that is afoot will likely affect cardiovascular conditions beyond pulmonary hypertension and blur the boundaries between specialists, he adds. While encompassing multiple organ systems, management strategies will at the same time need to be much more personalized to the quantified biomarkers and genetic predisposition of patients.
For pulmonary hypertension, “one-size-fits-all management ... gets you so far but it doesn’t get you all the way,” says Chan. “The idea that we can diagnose and treat based on markers that are very specific to the inflammatory programs that are driving disease is going to be essential to reaching that next level [of individualized care].”
Over the next few years, Chan will be leading a natural history study involving prospectively recruited pulmonary hypertension patients. The plan is to take longitudinal repeated measurements of blood biomarkers as well as brain tissue loss and weakened brain connectivity and to learn what is dynamic and possibly reversible, he says.
Meanwhile, Amlysion Therapeutics will work on raising funds to start developing next-generation drugs that activate NCOA7 to improve inflammation in pulmonary hypertension and other diseases, Chan reports. “My ultimate theory is that there are a number of different tissues that are communicating with each other that go beyond just the brain and the lung,” he says in hinting about forthcoming papers about other organ systems affected by the NCOA7 inflammatory pathway.
Besides Chan serving in the role of chief scientific officer, the small executive management team of Amlysion also includes a CEO whose identity has yet to be publicly disclosed. The company’s work is supported by the Harrington Discovery Institute at the University Hospitals in Cleveland, Ohio, which gave Chan a Scholar-Innovator Award earlier this year.
The award package includes a guaranteed grant of $100,000 over two years, the opportunity to compete for up to $300,000; the potential to qualify for mission-related investment funds typically up to $2 million; and a dedicated team of drug developers and project managers, regulatory assistance, intellectual property (IP) review, and business and clinical guidance. Chan and the University of Pittsburgh retain all IP rights.
“This is probably the most exciting set of science discoveries that I’ve ever been a part of,” says Chan. “As both a scientist and physician ... the whole reason I got into this field to begin with was to make the lives better for the patients whom I serve.”