Heritable Change: A $1,000,000 Private Gift Supports Research, Next Generation Leadership in MPS

A family faces a genetic condition with a nine-syllable name and meets a UNC doctor who studies it. The result has changed the way we treat the condition – and changed the outlook for people with it.

Heritable Change: A $1,000,000 Private Gift Supports Research, Next Generation Leadership in MPS click to enlarge The Bardsley family at Yosemite in 2008.
Heritable Change: A $1,000,000 Private Gift Supports Research, Next Generation Leadership in MPS click to enlarge Dr. Joseph Muenzer at work.

A rare and potentially fatal group of genetic diseases, mucopolysaccharidoses (MPS) afflicts one child in every 25,000 births. When that one person is dear to you, the diagnosis is a call to action. Catherine and Wayne Bardsley of McLean, VA want to transform the once-dire genetic heritage of MPS into a legacy of hope.  With a $1,000,000 gift honoring the memory of their son, they created the Jeffrey David Bardsley Fellowship in Pediatric Genetics and Metabolism and the Jeffrey David Bardsley Fund for Excellence in Research. The $500,000 fellowship will encourage the next generation of genetic physician scientists. The $500,000 research fund will support the ongoing work of Joseph Muenzer, M.D. Ph.D., professor of pediatric genetics at UNC-Chapel Hill, a world-renowned expert in MPS and the man who changed the Bardsleys’ lives forever.  

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Catherine Bardsley was just a girl when she learned to pronounce all nine syllables of mucopolysaccharidoses. It was an important word in her family. Her younger brother, Bill—whom she nicknamed “Biller”—was born in 1951 and soon displayed developmental delays. ”I remember knowing as a really little girl there was something different about Biller. I can’t tell you how many doctors my parents took him to who couldn’t diagnose him. He wasn’t technically diagnosed until he was six years old by doctors in Chicago, and they diagnosed him with the wrong form of MPS. We were told he had Hurler Syndrome. We believe he really had MPS II—Hunter Syndrome—which is what Jeff had.”  

MPS patients like Biller and Jeff are missing—or produce insufficient amounts of—the enzymes that break down and recycle cellular sugars called polysaccharides.  Because these sugars can’t be recycled, they remain in the cells, progressively damaging their function. Multiple systems are affected:  heart, bones, joints, respiratory system and central nervous system, resulting in stunted growth, difficulty breathing, heart irregularities, joint stiffness, and neurological complications. As the body ages and more sugars collect in the cells, problems grow worse over time.

Biller died of MPS just before his 21st birthday. Catherine and Wayne married and with an inkling she could be a carrier of MPS, they went to Johns Hopkins for genetic counseling.  She underwent amniocentesis when pregnant with their older son, Ed, and younger son, Jeff. Both came back negative for MPS. As Jeff aged, Catherine began to sense similarities between him and her brother. “When he was 1 ½, his pediatrician recommended he have a special urine test. It came back negative. But even when Jeff was a little guy and I held his hand, I remembered thinking there was something about him that reminded me of my brother.” Catherine was rubbing Jeff’s back one night when she felt pebbly lesions under his skin. A dermatologist ordered a biopsy. The diagnosis:  mucopolysaccharidoses. Jeff was nearly four years old.  A geneticist at Children’s National Medical Center in Washington, D.C. confirmed the dermatologist’s diagnosis. Catherine knew what to expect, and palliative care seemed the only option. Wayne responded to the family’s grief by launching a search for new knowledge in the field. “I wasn’t sure I wanted to re-immerse in that world,” Catherine said, “but Wayne started going to National MPS Society conferences. That’s where he met Joseph Muenzer.”

The accidental MPS geneticist

From 1960 – 1980, many students from Kalamazoo College in Michigan participated as “normal volunteers” in the Clinical Center at the National Institutes of Health in Bethesda, MD—college students who served as both subjects and research assistants on clinical trials. Joseph Muenzer was among them.  After earning his B.A. in chemistry at Kalamazoo and a Ph.D. in biochemistry and M.D. from Case Western Reserve University, he was eager to return to the NIH as a fellow. “My goal for the fellowship was to find a relatively rare disorder—one that would allow me to take care of patients and have a small research lab. Someone said, ‘There’s a researcher down the hall—Elizabeth Neufeld—and she may have a project for you.’”  Elizabeth Neufeld, Ph.D. studied the biochemistry of MPS, and indeed, she had a project for Muenzer: to clean up the purification of iduronate sulfatase—the enzyme missing in MPS II—and then attempt to clone the MPS II gene. At about the same time, a British researcher proposed a potential new treatment for MPS patients. They met with the researcher at the NIH, and though skeptical of the science, embarked on further study.  Budding scientist Joseph Muenzer recruited 30 to 40 MPS patients to the NIH and began a clinical trial. Although it proved unsuccessful, Muenzer gained new knowledge about the disease and invaluable clinical experience. Neufeld ask her protégé to contribute to an MPS chapter in a major genetics and metabolic textbook she had authored. She wrote the biochemistry portion, and Muenzer, the clinical portion. “The combination of seeing more MPS patients than most geneticists see in a lifetime and then writing the chapter with Elizabeth Neufeld established me as an ‘expert,’ even though I was only a fellow,” Muenzer said. “My story is such that I came to it by chance. Elizabeth Neufeld’s door could have been closed and I could have walked down the hall and been a pulmonologist or endocrinologist—those were the two halls on either side of her door.” 

With Neufeld as his mentor, Muenzer began his career as a physician scientist. Much of his early discovery took place not in the lab, but face-to-face. “These were patients virtually no one knew anything about,” said Muenzer. “We had a lot to learn. I developed a huge clinical expertise by basically talking to families and finding out what was causing their problems. Each child is a little different.” In the lab, Muenzer continued the research he began at the NIH – purifying the Hunter protein enzyme. In 1993, he joined the faculty at UNC-Chapel Hill as an associate professor in the Department of Pediatrics and developed a mouse model for MPS II. “A company called Transkaryotic Therapies used my mouse model to develop enzyme replacement therapy for Hunter Syndrome,” said Muenzer. “Because of that mouse model and my clinical experience with MPS, they selected me to be their principal investigator for their initial clinical trials. That’s when I began to work with the Bardsleys.”

“Would Jeff be interested?”

“It was one of the happiest days of my life when Dr. Muenzer called to ask if Jeff would participate in a Phase I/II clinical trial for MPS II,” Catherine said. Her son was 14 years old. It had been 40 years since Catherine’s brother died of MPS, and more than 10 years since Jeff was diagnosed—a long time without hope. Phase I ensured there were no adverse effects to the enzyme replacement therapy. Phases II and III evaluated efficacy. The study was double blind, and though the Bardsleys couldn’t be sure Jeff was receiving the therapy, they traveled to Chapel Hill every two weeks to get Jeff infused.  At first, they measured his progress in what wasn’t happening: Jeff wasn’t getting any worse. After a few more infusions, he began to improve. His spleen and liver grew smaller. The pebbling under his skin disappeared. With the benefit of ongoing infusions, Jeff continued to lead an active, relatively normal life. He played soccer, tennis and golf. He had close friends and went to sleep away camp. He graduated from the University of Richmond, earned a M.A. in accounting and worked as a financial analyst. Jeff joined the board of the MPS Society and enjoyed meeting affected kids. An aggressive cancer, and not MPS, brought his life to a close all too soon. He died in 2016 at the age of 28.

Changing the dynamic

Jeff’s obituary reads that enzyme replacement therapy is, “the standard, and only, treatment for Hunter Syndrome (MPS II).” Joseph Muenzer and Catherine and Wayne Bardsley are working to change that standard.  “We always regarded ongoing enzyme replacement therapy as an interim technology, an invaluable treatment but not a cure,” said Catherine. “The funds are intended to support research and build institutional knowledge regarding new treatments and, one hopes, ultimately a cure. We also want to do what we can to ensure that Dr. Muenzer’s efforts continue, and those of others who follow in his stead.”  

Because rare disorders attract little NIH funding, Joseph Muenzer’s current research is supported by private gifts—such as the Bardsleys’—and pharmaceutical companies. “I’m trying to develop therapies to treat the brain disease associated with MPS and also improve enzyme replacement therapy, which requires regular infusions. I have been putting the missing enzyme directly into the spinal fluid around the brain. Another trial will use gene therapy to have the enzyme continuously made in the body where it’s not currently being made.” Muenzer sees eight or so local MPS II patients, consults with patients across the country and has attracted a quarter to a third of the North American Hunter population to UNC-Chapel Hill over the past 10 years. He hopes the Bardsleys’ funds will help attract another passionate, talented physician scientist to the field. “One challenge of academic pediatrics is we don’t have funds to train residents to be medical geneticists. There’s not a lot of that kind of money out there, and it’s very hard to come by. It’s hard to recruit people, but this gift will help.”