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INNOVATION IN RETINA: Harvard’s Patricia A. D’Amore, PhD, MBA

A true pioneer in angiogenesis reflects on a prolific career.

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Patricia A. D’Amore, PhD, MBA, the Charles L. Schepens Professor of Ophthalmology, professor of pathology, and director of research at the Schepens Eye Research Institute of Mass. Eye and Ear at Harvard Medical School, ascribes much of her professional success to the fact that she never had a set career path and has always been open to interesting opportunities.

Dr. D’Amore was the first in her family to go to college. She tried a number of science-related summer adventures, including one “collecting bugs” at the University of Michigan field station in Cheboygan, which she decided was “fun, but not for me.” She always kept an open mind about where the future would lead her, even after she had obtained her PhD in biology.

“My PhD work with David Shepro got me hooked on vascular biology, but it wasn’t until I got to Johns Hopkins and had mentors like Drs. Arno Patz, Allen Fenselau, and Jerry Lutty, who were interested in this new concept of angiogenesis, that I appreciated the relevance of angiogenesis to ophthalmology,” she says.

FOLKMAN LAB EXPERIENCE

“In my postdoctoral work at Hopkins, we were doing protein biochemistry with the goal of isolating angiogenic factors that might be responsible for the abnormal vessel growth in eye diseases like proliferative diabetic retinopathy and wet macular degeneration,” recalls Dr. D’Amore. “Then, I got the opportunity to return to my hometown of Boston in 1981 and work in Boston Children’s Hospital as part of Dr. Judah Folkman’s Surgical Research Laboratory, which was then the heart of antiangiogenic research, both in oncology and ophthalmology.”

In the Folkman lab, Dr. D’Amore was considered “the ocular angiogenesis person” and along with Drs. Anthony Adamis, Joan Miller, David Shima, and others, was responsible for major breakthroughs in terms of identifying VEGF as a causal factor in retinal disease.

“We worked long hours, but we were young with few family obligations and we enjoyed the challenges that were presented to us.” says Dr. D’Amore. “It was an exciting time.”

While at the Folkman Lab, Dr. D’Amore was credited, along with Dr. Lois Smith, with developing a mouse model for oxygen-induced retinopathy in rodents.

“The model creates retinopathy of prematurity in mice,” she notes. “It’s become a standard test for researchers who are developing therapies for retinal disease and who want a way to determine their potential effectiveness preclinically.”

In recognition of their groundbreaking work in angiogenesis, in 2014 Dr. D’Amore was one of 7 co-laureates of the prestigious Antonió Champalimaud Vision Award.

Dr. D’Amore was also instrumental in bringing attention to pericytes by being the first lab to isolate and culture these capillary cells. Years later, the pericyte became the target of ill-fated anti-PDGF drugs that failed in clinical trials. In theory, the anti-PDGF agents would prevent the recruitment of pericytes and in doing so render the new vessel more dependent on VEGF, thereby optimizing the effectiveness of the anti-VEGF drugs.

“With anti-PDGF drugs, the goal was to amplify the effects of anti-VEGF therapies by preventing the pericyte from associating with the new vessels, rendering them more prone to the anti-VEGF. However, while the combination likely led to more vessel regression, the anti-PDGF would also lead to a lack of pericyte coverage would lead to vessel leakage; it is possible that these two effects just canceled either other out,” says Dr. D’Amore.

Patricia A. D’Amore, PhD, MBA
IMAGE COURTSEY OF PIERCE HARMAN

More recently, Dr. D’Amore’s studies have uncovered important physiological roles of VEGF, yielding crucial insight into the safe use of antiangiogenic therapies. Her ongoing investigations involve the role of the endothelial glycocalyx in the regulation of angiogenesis and the contribution of lipids to the pathogenesis of AMD.

EMPHASIS ON PATHOGENESIS

Citing her perspective as a biologist, Dr. D’Amore believes today’s companies are often too quick to put drugs into clinical trials, before the pathogenesis of the disease has been established. She has seen this rush to the clinic in dry AMD, a disease that she calls “a huge problem” and for which there is no FDA-approved treatment yet.

“I think we’ve seen that with failures in dry AMD trials using complement inhibitors,” she notes. “With anti-VEGF agents, we had strong preclinical evidence for a cause-and-effect relationship — where we knew that VEGF was a cause of pathologic leaky vessels and that anti-VEGF was able to counter it.”

Though anti-VEGF monotherapy with Lucentis or Avastin (Genentech) and Eylea (Regeneron) has been the mainstay of treating a range of common retinal diseases over the past decade, Dr. D’Amore says future advances in anti-VEGF may be limited to more patient-friendly delivery systems, incrementally more durable drugs such as brolucizumab (Novartis), and combinations such as anti-VEGF/Ang2, which she considers promising.

“That combination makes sense because the Ang1 stabilizes the vessels and the anti-VEGF also blocks the leakage,” she says.

KEYS TO MANAGING A SUCCESSFUL LAB

Dr. D’Amore says one of her main goals in directing a research lab is to create an environment in which employees are happy to be working there at the same time as developing confidence in their skills.

“Unhappy people can do good research, but I wouldn’t want to work in an unpleasant environment,” she says.

She has used the business skills she acquired in her MBA classes to become more effective at managing people. She ticks off a list of qualities that a good manager should possess.

“Being a good listener, giving constructive feedback — even when it is difficult to hear — developing workers’ confidence, having difficult conversations, giving your full attention to your people, demonstrating ability to develop new mentors, identifying strengths and weaknesses, helping with public speaking and encouraging better writing. Every young person needs mentoring. I was naïve at the beginning of my career. Others spent time mentoring me. I think it’s my obligation to pay it forward.”

HAPPY AT HARVARD

Asked if spending almost her entire career at a single institution was an advantage or disadvantage, Dr. D’Amore notes that while at Harvard she has been associated with Boston Children’s Hospital, Schepens Eye Research Institute, and Mass. Eye and Ear.

“I am exposed to other environments; I visit other institutions for seminars,” she notes. “I am a member of the Association of University Professors of Ophthalmology (AUPO). Maybe I don’t get that granular feel for another institution, but we get to compare notes quite a bit. It’s a big network, so I get a lot of variety.” RP