A researcher honors her mother’s legacy by searching for the first treatment for vascular dementia

Meredith Hay, PhD, professor of physiology, was in the midst of an exceptional scientific career, teasing apart the connection between the brain and the cardiovascular system, when she came to the University of Arizona in 2008.

At around that time, Dr. Hay’s mother was receiving treatment for breast cancer. The chemotherapy had devastating side effects.

“My mother had vascular dementia caused by her heart failure — and her heart failure was caused by her chemotherapy,” she said. “By the time the cardiologist figured out she had heart failure, her vascular dementia was so progressed. That’s actually what she died of. What was devastating was there was nothing they could do to stop or treat it.”

After Alzheimer’s disease, vascular dementia is the second-most common cause of dementia, and it currently has no FDA-approved treatments. That void in medical care deeply troubled Dr. Hay.

A few years later, she had a spark of inspiration during a conversation with Regents Professor of Psychology Carol Barnes, PhD, when she remembered work she did years earlier investigating a natural peptide’s influence on blood pressure. She wondered if it could be harnessed to improve blood flow to the brain and prevent or treat vascular dementia.

“Carol studies age-related cognitive impairment. I said, ‘Carol, tell me about older people with cognitive impairment. What happens if they have heart disease, hypertension or diabetes?’ Those diseases contribute significantly to cognitive impairment,” she recalled. “I had worked with angiotensin (1-7) years ago for hypertension, so I said, ‘Do you think it would be helpful for persons with vascular cognitive impairment?’”

That exchange laid the first stone on the path Dr. Hay has traveled since — one in which she has transformed angiotensin (1-7), a tiny peptide the body makes naturally, into a drug candidate that she hopes will become the first treatment for vascular dementia.

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“We started some experiments, and by golly, it worked. But you can’t take peptides orally — they break down really quickly,” she said. “We went to Robin Polt across Speedway and said, ‘Robin, can we make this a better drug?’ He made a whole series of peptides for us, and we tested them — and they work. That was really exciting.”

Her co-inventor, Professor of Chemistry and Biochemistry Robin Polt, PhD, slightly tweaked the chemical structure of angiotensin (1-7), improving its staying power in the body. They named it PNA5.

“It’s just a sugar attached to the peptide,” she said. “Once it’s in the body it gets broken down to sugar and the natural peptide you already have. It activates a sequence of activities that are protective in the brain.”

In labs across campus, U of A researchers have subsequently tested PNA5’s ability to influence the progression of conditions such as vascular dementia and Parkinson’s-related cognitive decline.

“The exciting thing about science is you do one experiment and you’re like, ‘That worked,’ and then you repeat it multiple times and it still works — and it works really well,” Dr. Hay said. “Then you give it to your colleagues, and it works in their models, so you know you have something. Then the question is, what does it take to take it from there to a human? What does the FDA require? It involves a lot.”

More than a decade of positive experiments has brought PNA5 to the verge of meeting humans outside the lab for the first time.

“I was convinced I was not going to spend any more time making mice feel better,” Dr. Hay said. Along with her co-principal investigators Todd Vanderah, PhD, professor and chair of pharmacology, and Craig C. Weinkauf, MD, PhD, associate professor of surgery, she has received a $9 million two-year grant from the National Institute on Aging, part of the National Institutes of Health, to kickstart first-in-human trials to test PNA5 for safety and side effects. They hope to begin trials later this year.

Despite reaching this major milestone, Dr. Hay says she almost doesn’t have time to celebrate her most recent success — because in science, researchers are always making their next move.

“You got to keep swimming,” she said. “We’re not resting. We’re furiously writing grants for the next round of studies to take it to the next level. It’s just one step after another.”

During every moment of this journey, Dr. Hay has kept her mother in mind.

“This work became deeply personal to me. Patients and their families have very few treatment options for vascular dementia,” she said. “It led me to ask whether we could protect the brain from damage caused by vascular and cardiac disease. That question — and my mother’s experience — is a major reason I have spent so many years developing PNA5.”

Meredith Hay, PhD, is a scientific founder and equity holder of ProNeurogen, Inc. The work presented here was conducted independently, and all relationships have been managed in accordance with University of Arizona conflict-of-interest policies. Many University of Arizona faculty and staff have contributed to the discovery and development of PNA5, including early scientific and clinical work by Professor of Chemistry and Biochemistry Robin Polt, PhD, Professor of Physiology John Konhilas, PhD, Clinical Research Coordinator Christina Hoyer-Kimura, PhD, Associate Professor of Physiology Paulo Pires, PhD, and Director of the Evelyn F. McKnight Brain Institute Carol Barnes, PhD; additional studies on Parkinson’s-related cognitive decline by Professor of Neurology Lalitha Madhavan, MD, PhD, Research Professor of Neurology Torsten Falk, PhD, and Postdoctoral Research Associate Kelsey Bernard, PhD; and additional studies on chronic pain by Dr. Vanderah.