Families Push Research Forward in Rare Diseases

This story was supported by a grant from the National Press Foundation in partnership with Fondation de France. For the main story on how mRNA is being investigated for its potential in rare diseases, click here.

Kathy Stagni first met Charles Venditti, MD, PhD, at a meeting of her organization, the Organic Acidemia Association, more than 20 years ago.

Stagni's daughter had been born with a rare disease called propionic acidemia (PA) a little more than a decade earlier, and she had long been pushing to increase the visibility and scientific interest in the condition.

At the time, Venditti was a fellow at Children's Hospital of Philadelphia (CHOP), where he was the only postgrad focused on metabolic conditions. That's where he started meeting dozens of families whose children had organic acidemias and other metabolic emergencies.

"Our families just clung onto him" at the conference, Stagni told MedPage Today. "They were saying, please, study our disorders!"

Now, Venditti is the head of the Molecular Medicine Branch at the National Human Genome Research Institute (NHGRI) of the NIH. He said he wouldn't have gotten there without the help of the families he's encountered along the way.

"I always think back to the days when I was starting off in this work. It was really the patients who supported me, listened, and said, 'We believe in you,'" Venditti told MedPage Today. "That really gives people in the research space the boost of confidence to go forward. It's critical."

There's a unique funding model in rare diseases. These conditions typically involve small patient populations, so they don't attract attention from large pharmaceutical companies looking to develop the next blockbuster drug. Often, families are left to do the fundraising on their own, to support the basic science research that would help advance treatments for their child's condition.

The model was portrayed perhaps most famously in the film "Extraordinary Measures," which told the story of John Crowley, a father who quit his job in order to dedicate his life to finding a treatment for his kids' Pompe disease. Crowley is now the executive chairman of Amicus Therapeutics, a biotech company focused on developing therapies for rare diseases.

More recently, families have raised money to design and test their own antisense oligonucleotides targeted to their kids' conditions.

Emil Kakkis, MD, PhD, the founder and CEO of the biotech Ultragenyx, wrote a book, Saving Ryan, about his experience developing a therapy for the rare disease of mucopolysaccharidosis type I (MPS I). Kakkis, who at the time was an academic researcher, became very close with his patient, Ryan, and Ryan's family, who also raised money to push the science forward.

Their work together led to the approval of the enzyme replacement therapy laronidase (Aldurazyme), the first treatment for MPS I, in 2003.

In 2017, Ultragenyx won FDA approval of its enzyme replacement therapy vestronidase alfa-vjbk (Mepsevii), the first treatment for MPS type VII, which affects only about 20 patients in the U.S.

"We were able to [develop this drug] because we were really attuned to how to do it," Kakkis told MedPage Today. "But the truth is, I can't even do it again because the cost of doing that is still prohibitive and the product will barely survive making money. It will probably break even, and you can't build a company on those economics."

"I think it's a failing of us, companies, and academia and FDA, to not have figured out an efficient way of getting those kind of rare diseases treated, to leave parents to have to develop their own drugs," he added.

When Venditti was starting his career, many of his mentors told him not to pursue rare metabolic disorders as a research career.

"Decades ago, people said these are not treatable disorders; do not study methylmalonic acidemia," Venditti said.

But Venditti had already developed a deep concern for the families he'd met at CHOP and at conferences. Among the most common conditions he saw during his fellowship, he said, were methylmalonic acidemia (MMA), cobalamin utilization disorders, and PA.

He remembers one patient in particular who helped him see a way forward. This patient had such a severe form of MMA that he had a liver transplant at age 2. One day Venditti got a call from the child's father, who was concerned because the child was spiking a fever of 104 degrees.

The boy was admitted to the hospital, and Venditti ran down to see him.

"He wasn't getting aggressive fluid replacement or adequate calories, which are critical to maintain patients with MMA," Venditti said. "But I just couldn't believe how stable he was. ... I'd taken care of many patients who were so sick from mild perturbations like a cold or a mild respiratory syndrome, and it was striking to witness that a patient with a 104 fever, receiving minimal support, was totally fine."

"At that point, I knew the way to treat these patients would be to try to develop gene and cell therapies that target the liver," he said.

Venditti made the case for pursuing gene therapy for MMA with his chair of genetics, who opened up space in his laboratory for the young researcher.

Families raised money for Venditti, too. "That's what really started me on this pathway, that interaction with families from CHOP who encouraged me to do research," he said.

He also won an NIH career development award at the end of his fellowship -- but not long after, the NIH intramural research program came calling. The NHGRI offered Venditti the support to develop a clinically focused program on MMA and cobalamin utilization disorders while, in parallel, developing animal models and working on biochemistry and molecular genetics.

It was bittersweet to leave CHOP and his early career grant, he said, but since he saw his first patient at the NIH in 2004, he and his colleagues have sponsored more than 1,300 patient visits. In 2016, he was able to expand the program to include PA as well.

His team is currently conducting natural history studies focused on both MMA and PA. With his laboratory colleagues, he has led the development of a "whole suite of new genomic therapeutics to treat MMA," including an mRNA therapy, a nuclease-free genome editing treatment, and conventional adeno-associated viral (AAV) vector gene therapy. In partnership with the National Center for Advancing Translational Sciences, and the National Institute of Neurological Disorders and Stroke, he is helping with an initiative called Platform Vector Gene Therapy (PaVe-GT) to facilitate the development of AAV gene therapy for rare genetic disorders, including PA.

"The paradigm of MMA being regarded as an untreatable disorder has dramatically changed. We are now assessing three new advanced genomic therapies that might be effective for patients," he said.

Venditti emphasized the importance of the partnerships he had with the patients and their families for making all of his work possible.

"It has been inspiring to work with the families and have them support our efforts," he said. "We would never be where we are without them."

Stagni echoed his sentiments: "He's developed a great team at the NIH and he tries to incorporate parents' views into everything he does," she said. "I think he really worries about his patients, as well as the parents, and what we have to endure daily."

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