40 Years of Cystic Fibrosis: A Long Journey From the Discovery of the CFTR Gene to the Use of CFTR Protein Modulators and Beyond

Dear Colleagues,

The earliest clinical observations of cystic fibrosis (CF) date back to the seventeenth century, when the only evidence came from deceased children in whom unusually high levels of salt were found on the skin—as an ancient seventeenth-century German proverb went: "Woe to that child which when kissed on the forehead tastes salty. He is bewitched and soon must die." It was not until 1938 that Dr. Dorothy Andersen published the first scientific article describing cystic fibrosis of the pancreas, based on autopsies performed on children of that era. These studies revealed fundamental features of the disease, including elevated skin’s salt concentration, pancreatic fibrosis, the presence of cysts (from which the term "cystic fibrosis" derives), and malnutrition.

In 1948, Dr. Paul di Sant'Agnese made further advances that led to the development of the "sweat test," still used today as the gold standard for diagnosing the disease.

Thirty-seven years have passed since the landmark discovery of the gene responsible for cystic fibrosis (CF)—CFTR in 1989, yet CF research appears far from over. From the painstaking positional cloning that first revealed the CFTR channel defect to the rational design of small-molecule correctors and potentiators—culminating in highly effective modulator therapies that have reshaped survival curves and quality of life for the majority of people with CF—CF research stands as a compelling example of how basic science translates into clinical revolution. This Special Issue, 40 Years of Cystic Fibrosis: A Long Journey from the Discovery of the CFTR Gene to the Use of CFTR Protein Modulators and Beyond, invites the submission of original research articles, systematic reviews, and perspective pieces that document, deepen, and expand the critical development in modern medicine.

In this highly effective modulator era, significant challenges persist: no approved modulators are available for patients carrying CFTR nonsense mutations; finding modulators for new and rare CFTR variants; questions surrounding optimal medication usage; chronic lung infection; and emerging complications including CF-related diabetes, liver disease, and mental health burden as the population ages.

We welcome contributions spanning the full breadth of CF research, including but not limited to: molecular and structural biology of CFTR; genotype–phenotype correlations, genetic modifiers and variant-specific therapies; novel therapeutic strategies such as gene editing, mRNA delivery, and read-through agents; CF model development; microbiology, inflammation, and lung immunity in the context of modulator treatment; multiorgan involvement and emerging comorbidities; real-world outcomes, health economics, and patient-reported measures; and the evolving challenges of newborn screening and reproductive counseling in a new therapeutic landscape.

This is a unique opportunity to contribute to a curated collection that will serve as both a historical milestone and a forward-looking roadmap for researchers, clinicians, and the CF community worldwide. We encourage submissions that not only reflect on how far the field has come, but that chart the course for the decades ahead.

Prof. Dr. Felice Amato
Dr. Valeria Rachela Villella
Dr. Yunjie Huang
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

• CFTR variants
• CFTR modulators
• genetic modifiers
• CF therapy
• CF models
• gene-therapy