Researchers at the University of Arizona College of Medicine – Tucson have been following a tiny peptide called PNA5 for more than a decade, starting from its birth in the laboratory and cheering it along as it endured a battery of tests in petri dishes and animal models.

Every step of the way, PNA5 suggested an ability to protect brain cells, and its developers hope it will pass the final tests: clinical trials that may ultimately evaluate its efficacy in treating certain types of dementia and cognitive decline.

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The peptide's co-inventor, Meredith Hay, is focusing on vascular dementia, which currently has no treatments other than lifestyle changes. By the time someone receives a diagnosis, Hay says, these are "too little, too late."

"Patients are in desperate need of an effective treatment, and we are doing everything we can to help find that treatment," said Hay, a professor of physiology. "The greatest reward would be to see a safe and effective treatment for people who currently have very few options."

A closer look at vascular dementia

Multiple conditions, such as strokes, hardening of the arteries, hypertension and diabetes, can damage blood vessels, which reduces blood flow to the brain. Vascular dementia arises when the brain is starved of oxygen, which can result in a cycle in which brain tissue is damaged by both the lack of oxygen and the resulting inflammation.

"Inflammation is part of the body's natural repair system. If you have an injury, inflammation helps the healing process," Hay said, explaining how the tissue damage caused by reduced oxygen in the brain kickstarts the inflammation process. "The problem occurs when inflammation does not switch off. In vascular dementia, the brain's resident immune signals can remain activated."

In addition to harming brain tissue, persistent inflammation can damage the blood-brain barrier, which protects the brain from harmful substances. When that happens, a gateway is opened to further inflammatory signals, which can wreak even more havoc in the brain. This sinister feedback loop makes vascular dementia untreatable by the time it's entrenched and tissue damage is widespread.

A novel peptide is born

Hay hopes this feedback loop can be interrupted by PNA5, which is based on a protective peptide the body naturally makes but is engineered to be more effective in the brain. Previous lab studies showed PNA5 could improve blood flow and decrease inflammation in the brain, leading to improved cognitive performance.

"Our work focuses on trying to intervene before irreversible loss of brain function. Our goal is not to suppress the entire immune system – PNA5 is intended to restore balance to keep the brain healthy," Hay said. "Our drug acts on both sides of the blood-brain barrier – a drug given to treat the brain needs to be able to cross that barrier."

PNA5 enters the brain when it attaches to a receptor, as if it were opening the front door to the brain by inserting a key into a lock. Unlocking the door triggers a cascade of chemical reactions that increase oxygenation and decrease inflammation in the brain.

The researchers hope this will help treat not just vascular dementia, but also other conditions caused by inflammation, and that someday additional funding will enable them to test PNA5 for Parkinson's-related cognitive decline, postoperative cognitive impairment and chronic pain.

"These are different conditions, but they share aspects of vascular dysfunction and maladaptive inflammation," Hay said. "PNA5 may provide a way to address that common biology."

Putting PNA5 to the test – and into the clinic

Hay hopes her fledgling molecule will spread its wings in a Phase 1 trial that is slated to begin later this year, funded by a $9 million two-year grant from the National Institute on Aging, part of the National Institutes of Health. Sixty healthy volunteers will receive subcutaneous injections of PNA5 at increasing doses to assess safety and side effects.

If PNA5 passes Phase 1, the team hopes to advance to Phase 2 later in 2027, testing the drug in a larger group of volunteers to determine efficacy in treating vascular cognitive impairment and dementia.

By the time Phase 1 trials start, Hay will have devoted nearly 15 years of her career to shepherding PNA5 through each stage of discovery and development.

"There are no shortcuts in this process. Each step has built the evidence needed to justify the next one. This award builds on over $16 million in earlier NIA support – the preclinical development, toxicology, manufacturing and regulatory work needed to reach this point," said Hay, who is principal investigator of the Phase 1 trial, along with Todd Vanderah, professor and chair of pharmacology, and Dr. Craig C. Weinkauf, associate professor of surgery.

As co-inventor, Hay worked with Tech Launch Arizona, the commercialization arm of the university, to patent the technology and license it to ProNeurogen, Inc., a startup she co-founded to advance PNA5 to the clinic.

Hay, who also has appointments at the McKnight Brain Institute and BIO5 Institute, says she feels tremendous satisfaction seeing her drug candidate finally advance to this point, where it will be meeting humans outside the lab for the first time.

"The most rewarding part is seeing a basic scientific observation move toward something that could eventually help patients and families – that's what gets me up every day," she said. "It's exciting, but also very humbling. When you have worked on something for this long, reaching a clinical trial is not a victory lap – it's the beginning of a new and much more demanding test."

This research is supported by the National Institute on Aging of the National Institutes of Health under Award Nos. 1UG3AG104642, U01AG066623 and U01AG082617.