University of Iowa Health Care pulmonologist David Stoltz, MD, PhD, and his colleagues have been awarded
a five-year, $11.8 million grant from the National Heart, Lung, and Blood Institute, part of the National Institutes of Health, to study the pathogenesis and therapeutic approaches for primary ciliary dyskinesia (PCD), a rare genetic disorder characterized by chronic respiratory tract infections.
An often-misdiagnosed condition
PCD is caused by mutations in more than 50 different genes. It is a rare condition, affecting 12,000 to 17,000 people in the U.S., according to the American Lung Association.
With PCD, the cilia—the tiny hairlike structures that move mucus and other debris out of the lungs and airways—do not work properly. As a result, patients develop chronic infections that lead to breathing and sinus difficulties.
PCD symptoms are often attributed to other lung and respiratory problems. Unlike cystic fibrosis, for example, babies aren’t screened for PCD at birth, which means that most people with PCD typically aren’t diagnosed until they’re young children or, in some cases, adults.
“While PCD tends to be less fatal than cystic fibrosis, progressive lung and sinus disease impacts quality of life and, in some cases, leads to early respiratory failure,” says Stoltz, who is a professor of internal medicine and the director of the pulmonary, critical care, and occupational medicine division in the Carver College of Medicine Department of Internal Medicine.
"It’s similar to cystic fibrosis in that, up until a couple of years ago, all the treatments were symptomatic, and none of the treatments were aimed at fixing the disease," Stoltz says. “We’re hoping the research funded by this grant will help change this."
Three projects looking at PCD
With the research grant, Stoltz and colleagues will use a similar approach to research at Iowa that led to breakthroughs in understanding the pathogenesis and development of treatments for cystic fibrosis.
Researchers at Iowa and from the University of Missouri will focus on three projects. The first will use an animal model to understand the early development of sinus and lung disease in PCD. Mouse models have limitations for studying PCD because they "don't get lung disease like people with PCD,” Stoltz says, so the research team created a pig model with a disruption to the DNAI1 gene.
“This is very powerful in terms of looking at what are the initial stages and first steps in the disease pathogenesis, how does it start and progress, and can we intervene in different ways over time,” Stoltz says.
The second project will look at what happens to cellular metabolism when cilia function is impaired by PCD. The third project will determine if DNAI1 gene addition to ciliated epithelial cells can repair and restore cilia function, which would affect disease development and progression.
Important funding for a rare disease
This grant is important for studying a rare disease that has garnered limited research funding, according to Stoltz. He believes the research team can build on the success of their cystic fibrosis work, which also included a pig model, to offer hope for people with PCD. While symptoms can be treated for individuals with PCD, there is no cure for the underlying disease.
“It’s similar to cystic fibrosis in that, up until a couple of years ago, all the treatments were symptomatic, and none of the treatments were aimed at fixing the disease," Stoltz says. “We’re hoping the research funded by this grant will help change this.”
Along with Stoltz, UI researchers on the project include Joseph Zabner, MD; Michael Welsh, MD; Paul McCray, MD; Patrick Sinn, PhD; David Meyerholz, DVM, PhD; Alejandro Pezzulo, MD; Mahmoud Abou Alaiwa; MD; Anthony Fischer, MD, PhD; Yuliang Xie, PhD; Miles Hagner, MD; and Eric Taylor, PhD.