Research Advances Cell/Gene Therapy for Cystic Fibrosis

At a glance:

• Researchers use stem cell technology to create ionocytes, recently discovered airway cells involved in cystic fibrosis.
• Scientists can now study ionocytes in the lab and explore their potential for CF treatment.
• Such treatments could one day offer alternatives to standard therapy of CFTR modulators, which do not work in all patients.

In 2018, two studies published in Nature rocked the cystic fibrosis scientific community. They found that the gene mutation that drives cystic fibrosis primarily affects ionocytes - previously unknown cells that make up just 1 percent of cells in the airway.

Surprisingly, these rare cells were making more than 90 percent of the protein that's diminished in the disease: cystic fibrosis transmembrane conductance regulator, or CFTR for short.

Now, in the American Journal of Respiratory and Critical Care Medicine, researchers at Harvard Medical School, Boston Children's Hospital, and Boston University report creating ionocytes from patients for the first time using stem cell technology.

The accomplishment means that ionocytes can now be studied in a dish to understand their biology - and their possible use as a treatment vehicle.

"Maybe we could correct patients' ionocytes and put them back in the lungs," said Ruby Wang, HMS assistant professor of pediatrics at Boston Children's. "This is why it's exciting."

Wang and Benjamin Raby, the HMS Leila and Irving Perlmutter Professor of Pediatrics and chief of the Division of Pulmonary Medicine at Boston Children's, envision developing a cell therapy or gene therapy that targets ionocytes.

Such a therapy would offer an alternative to CFTR modulators, which can treat cystic fibrosis by improving the movement of chloride and water and moistening mucus secretions. Despite being a breakthrough for cystic fibrosis treatment, these drugs are expensive, don't work in all patients with cystic fibrosis, and have side effects and interactions with other drugs; and people who do respond to CFTR modulators must take them for a lifetime.

Overturning dogma in cystic fibrosis

The idea that ionocytes could play a key role in cystic fibrosis initially sparked intense skepticism. How could such an uncommon cell help keep the lungs clear? The airway's ciliated cells, which propel mucus along the airways, seemed like the logical cell to target.

"When I was in medical school, the gospel was that the CFTR mutation was in the ciliated cells," said Wang. "We didn't know about ionocytes at the time and didn't expect to make them."

But to their surprise, they did.

Starting with patients' blood cells, Wang and colleagues created induced pluripotent stem cells.

They then directed the stem cells to differentiate in a stepwise fashion, first generating airway basal-like cells, or iBCs, through a previously published protocol.

Unexpectedly, modifying the protocol and stimulating the iBCs yielded ionocytes with high levels of the CFTR protein.

In a dish, the ionocytes have long extensions a bit like neurons. That has led the researchers to speculate that the ionocytes might be talking to and influencing other cells.

Wang thinks it will take more time to tease out exactly what they do.

"Now we need to find out ionocytes' developmental origin and function," she said. "That's hard to study because they're so rare."

A cell therapy initiative

Wang's work is part of a larger effort underway at Boston Children's. With collaborators in the Stem Cell Research Program - Carla Kim, professor of genetics in the Blavatnik Institute at HMS and HMS professor of pediatrics at Boston Children's; Thorsten Schlaeger, HMS instructor in pediatrics at Boston Children's; and George Daley, the Caroline Shields Walker Professor of Medicine at HMS and Boston Children's - she and Raby have formed the Pulmonary Cellular Therapeutics Initiative to seek alternative therapies for lung diseases.

With the most relevant affected cells already in hand, as well as a human cell-based platform for studying them, cystic fibrosis could be the first test case.

Authorship, funding, disclosures

Additional authors are Schlaeger, Yang Tang, Stuart Rollins, and Chantelle Simone-Roach of HMS and Boston Children's; Jonathan Lindstrom-Vautrin, Feiya Wang, Pushpinder Singh Bawa, Mary Lou Beermann, and Finn J. Hawkins of BU and Boston Medical Center; Junjie Lu and John Mahoney of the Cystic Fibrosis Foundation Therapeutics Laboratories; Steven M. Rowe of the University of Alabama at Birmingham; and Darrell N. Kotton of BU, BMC, and the University of Alabama at Birmingham.

The work was funded by the Cystic Fibrosis Foundation and by the Fred and Gilda Slifka Funds and CF/MS Funds.

Adapted from a Boston Children's blog post.