Michigan State University College of Human Medicine professor and a Helen DeVos Children’s Hospital physician have joined forces to study a rare genetic disease that, until recently, was completely unknown. Their combined efforts have resulted in a novel disorder diagnosis, a therapeutic treatment and – now – a five-year, $4M National Institutes of Health grant to further their research and understanding.

The collaboration between the two scientists – André Bachmann, an MSU professor of pediatrics, and Caleb Bupp, a medical geneticist at the Corewell Health-affiliated children’s hospital in Grand Rapids, Michigan – grew out of the case of a 3-year-old girl whose symptoms included complete hair loss, an enlarged head, low muscle tone and developmental delays.

Bupp recalled that he and other physicians couldn’t figure out what condition she had, although a genetic test revealed a mutation in a gene called ornithine decarboxylase 1, or ODC1.

As fate would have it, just a couple of blocks away from the children’s hospital, there happened to be an ODC1 expert with 30 years of research experience studying this gene and its role in an often-fatal childhood cancer called neuroblastoma. That expert was Bachmann, associate chair for research in MSU’s Department of Pediatrics and Human Development.

Bupp learned of Bachmann’s research into the ODC1 gene during a co-presentation by Bachmann and Surender Rajasekaran, a pediatric intensive care physician at Helen DeVos Children’s Hospital and assistant professor of pediatrics at MSU. During the presentation, Bupp learned that when mutated, ODC1 can trigger an overproduction of polyamines, a natural compound found in all life-forms.

“That was the first time I heard this word, ‘polyamines,’” Bupp said. That presentation led to a collaboration that, ultimately, resulted in the designation of a new disorder: Bachmann-Bupp syndrome.

Years earlier, Bachmann had discovered that a drug called difluoromethylornithine, or DFMO, which was developed in 1978 first as an anticancer drug and later used for treating African trypanosomiasis also known as African sleeping sickness, could be repurposed to treat neuroblastoma.

In children with neuroblastoma, the overproduction of polyamines in cancer cells causes the cancer to grow.

Polyamines are “important in making cells properly grow,” Bachmann said, adding: “If you have too much of one polyamine or too little of another, things go awry.”

Bachmann’s research showed that DFMO turned down the production of polyamines in neuroblastoma cells. The drug is now in clinical trials as a treatment for neuroblastoma at pediatric hospitals all over the country.

Although Bupp’s patient does not have cancer, the mutation in her ODC1 gene caused her body to accumulate lots of toxic levels of the ornithine decarboxylase enzyme, or ODC, which triggered a buildup of polyamines in all her cells.

Expanding research through discovery

With single-use compassionate authorization by the Food and Drug Administration, Bupp began giving his patient frequent doses of DFMO. The time from discovery of the syndrome to the first dose was less than two years, an unusually quick turnaround. Five years later, the patient who is now 7 years old has made significant developmental progress, has gained muscle tone, is able to feed herself, and has grown a full head of hair, Bupp said.

Since the discovery of that first case, Bupp and Bachmann have become aware of 11 other patients worldwide with Bachmann-Bupp syndrome, and they suspect many more are undiagnosed.

The federal grant will allow them to continue studying the syndrome as well as other polyamine-related genetic disorders like Snyder-Robinson syndrome. That portion of the research will be led by Robert Casero, a professor of oncology at the Johns Hopkins University School of Medicine. 

Bupp will continue to see patients at the children’s hospital and collect samples for analysis in Bachmann’s lab.

Many questions remain that the pair hope to solve through this growing collaboration. What is the proper dose of DFMO? Is there a better drug for treating the syndrome? What other metabolic pathways in the body are affected by the ODC1 mutation? And what other polyamine syndromes are yet to be discovered? 

To further their research, Bachmann, Bupp and Rajasekaran founded the International Center for Polyamine Disorders, a joint venture by MSU and Corewell Health, formerly Spectrum Health. The center is expected to become a worldwide information hub for physicians and parents of patients diagnosed with polyamine-related disorders.

Both Bupp and Bachmann insist the collaboration between MSU and Corewell Health is essential for medical research to translate into the clinic.

“It’s absolutely key,” Bachmann said. “Nobody these days can do it alone.”

“We have the patients, and MSU doesn’t; MSU has the basic science, and we don’t,” Bupp added. “I can’t think of a better way to do what we’re doing. This kind of work is the sort of thing that takes a village.”