Abstract
Thirty-one years ago on September 8, 1989, Jack Riordan and his colleagues published in Science the discovery of the cystic fibrosis (CF) gene encoding the CF transmembrane conductance regulator (CFTR). 1 This landmark paper, with more than 5,400 citations to date, paved a fascinating journey toward the cure for all CF sufferers—a journey that was, and to some extent still is, in the words of the renowned Greek poet Constantine Cavafy “…full of adventure, full of discovery.” 2 Over a span of three decades, we have witnessed groundbreaking successes by pioneering researchers and clinical scientists in their common pursuit to cure CF.
Featured in this special issue is a commentary by the United Kingdom CF Gene Therapy Consortium that shares with our readers their lessons learnt when progressing into the clinic non-viral- and, more recently, viral-based molecular therapeutics for CF. They highlight the complexities of gene therapy versus genome editing, the challenges of choosing the right subject population, the need to incorporate appropriate clinical outcome measures, and the need to tackle the heated debate surrounding the cost of goods.
I am delighted to feature in this issue an insightful and thought-provoking interview with Dr. Mike Boyle, the chief executive officer of the Cystic Fibrosis Foundation (CFF). The CFF's approach of funding innovative therapies, which has set the example that many other disease-focused foundations have followed, has been instrumental in the development of therapeutics for CF, all while supporting the health and well-being of CF patients in the United States and worldwide. Dr. Boyle highlights the groundbreaking impact of novel technologies funded by the CFF and the visionary strategy of the CFF to continue to fund the development of innovative molecular therapies. He discusses the bold forward-thinking strategy of the CFF and its early financial investment in the development of modulators. Many considered the investment a risky approach, but it was in fact a well-thought-out strategy that paid off, with the recent approval of Trikafta™—a three-drug combination that restores CFTR function at functional levels in CF patients with at least one ΔF508 CFTR mutation, the most prevalent CFTR mutation. Trikafta™ is now a treatment option for almost 90% of CF patients worldwide. True to its core values and its mission of making CF stand for “cure found,” the CFF shifted its focus to strategically supporting several novel molecular therapies designed to treat the remaining ∼10% of CF patients.
In this special issue, we include six reviews from internationally renowned CF researchers, addressing the most pressing issues that are central to the development and clinical translation of molecular therapeutics. Vu and McCray review the current state of gene therapy and gene-editing approaches for various genetic respiratory diseases that include CF, α-1 antitrypsin deficiency, and surfactant protein deficiencies. Carneiro et al. review the barriers that hinder clinical success in lung-directed gene therapy. They also discuss technological advancements to create engineered adeno-associated virus (AAV) capsid variants with an improved tropism for the airway, a favorable immunologic profile, and which have the ability to overcome the physical barriers of the lung. Da Silva Sanchez et al. review the current state of mRNA and CRIPSR therapeutics, and highlight several important issues that are central to the successful development and subsequent clinical translation of these therapeutics for CF. In the same subject area, King et al. review the current state of genome editing for the CF airway, and provide an insightful overview of this exciting technology designed to treat CF patients who are not amenable to the current modulator therapeutics. The authors highlight the importance of a long-lived correction of the CFTR defect as a result of efficiently targeting and editing the basal stem/progenitor cells. Brommel et al. review the use of AAV as a technical platform for genome editing to deliver safely and efficiently DNA transposons, homologous recombination templates into safe harbors, and nucleases for targeting integration that facilitates sustained correction of the CFTR defect. Central to the translation of any lung-directed therapeutic is the noninvasive assessment of a therapeutic benefit. Parsons and Donnelley discuss the technological advancements that facilitate invaluable and, with impressive detail, noninvasive imaging of the airways (highlighted in this issue's cover illustration). This technology is predicted to become fundamental in assessing the therapeutic outcomes of the technologies featured in this issue.
Guest editing this special issue on CF has provided me with the incredible opportunity to highlight the dedication, perseverance, and innovation of my fellow CF researchers; to applaud the adaptability of the national and international CF research communities; and to recognize the leadership of the CFF in their unwavering mission of supporting programs to find the cure for all CF mutations. Watch this space for what is certainly going to be an exciting few years ahead!