Review
Cell Biology
Isabelle Fajac, Isabelle Sermet
Summary: Cystic fibrosis is a severe genetic disorder caused by mutations in the CFTR gene. New drugs called CFTR modulators aim to restore the function of the CFTR protein, but some patients with rare mutations are not yet eligible for this treatment. Various approaches are being pursued to expand the range of mutations eligible for CFTR modulators and develop new therapies for mutations that do not produce CFTR protein.
Review
Pharmacology & Pharmacy
Hongshu Sui, Xinghua Xu, Yanping Su, Zhaoqing Gong, Minhua Yao, Xiaocui Liu, Ting Zhang, Ziyao Jiang, Tianhao Bai, Junzuo Wang, Jingjun Zhang, Changlong Xu, Mingjiu Luo
Summary: This review examines the history and recent advancements in cystic fibrosis (CF) gene therapy, including CRISPR-based gene editing strategies. The challenges of airway transduction vectors, large animal CF models, the complexity of CF pathogenesis, and heterogeneity of CFTR expression in airway epithelium are discussed along with future prospects.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Nicole Reyne, Patricia Cmielewski, Alexandra McCarron, Juliette Delhove, David Parsons, Martin Donnelley
Summary: The study evaluated the effect of lentiviral-mediated CFTR airway gene delivery on nasal PD in a CFTR knockout rat model, showing that the gene therapy resulted in a mean correction of 46% towards wild-type chloride response in treated CF rats.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Sateesh Krishnamurthy, Soumba Traore, Ashley L. Cooney, Christian M. Brommel, Katarina Kulhankova, Patrick L. Sinn, Gregory A. Newby, David R. Liu, Paul B. McCray
Summary: The study found that using adenine base editor RNPs can successfully correct certain gene mutations causing CF, with repair efficiencies reaching 38-82%, achieving functional correction of CFTR-dependent channel activity.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Critical Care Medicine
Shan Wang, Suchan Niroula, Ashley Hoffman, Melika Khorrami, Melina Khorrami, Feng Yuan, Grace N. Gasser, Soon Choi, Bovey Liu, Justin Li, Mark L. Metersky, Matthew Vincent, Christopher P. Crum, Richard C. Boucher, Harry Karmouty-Quintana, Howard J. Huang, Ajay Sheshadri, Burton F. Dickey, Kalpaj R. Parekh, John F. Engelhardt, Frank D. McKeon, Wa Xian
Summary: CF patients' lungs harbor proinflammatory stem cell variants that contribute to persistent inflammation and are resistant to CFTR modulator therapy.
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
(2023)
Review
Medicine, Research & Experimental
Nilofer Sayed, Prince Allawadhi, Amit Khurana, Vishakha Singh, Umashanker Navik, Sravan Kumar Pasumarthi, Isha Khurana, Anil Kumar Banothu, Ralf Weiskirchen, Kala Kumar Bharani
Summary: Gene therapy is a method to treat diseases by silencing, replacing, or editing genes. The transfer of genes can be done through transformation, transduction, or transfection using physical, chemical, or biological methods. Gene therapy has been used in various diseases, but the safe and effective delivery of genes remains a major challenge.
Article
Biochemical Research Methods
Samuele Ferrari, Stefano Beretta, Aurelien Jacob, Davide Cittaro, Luisa Albano, Ivan Merelli, Luigi Naldini, Pietro Genovese
Summary: BAR-Seq is a strategy for tracking edited cells that allows clonal tracking analyses without the need for computational resources or advanced bioinformatic skills, and can be used to investigate the clonal dynamics and behavior of edited cells in different environments.
Review
Pharmacology & Pharmacy
Douweh Leyla Gbian, Abdelwahab Omri
Summary: This paper reviews current treatments of CF that mitigate symptoms and target genetic defects. The use of gene and drug delivery systems such as viral or non-viral vectors and nano-compounds to enhance CFTR expression and the activity of antimicrobials against chronic pulmonary infections respectively, will also be discussed. Nano-compounds tackle biological barriers to drug delivery and revitalize antimicrobials, anti-inflammatory drugs and even genes delivery to CF patients.
EXPERT OPINION ON DRUG DELIVERY
(2021)
Article
Pharmacology & Pharmacy
J. Mercier, M. Ruffin, H. Corvol, L. Guillot
Summary: Cystic fibrosis is a rare genetic disease that mainly affects the lungs, but patients' life expectancy has increased due to advancements in patient care and development of new drugs. Gene therapy remains an attractive alternative despite the development of CFTR correctors and potentiators.
FRONTIERS IN PHARMACOLOGY
(2021)
Review
Pharmacology & Pharmacy
Yuan Ding, Chenyang Wang, Zhongquan Sun, Yingsheng Wu, Wanlu You, Zhengwei Mao, Weilin Wang
Summary: MSCs have been proposed as a novel tool against cancer due to their tumor homing and immune privilege characteristics. Nonviral vectors have emerged as a potential solution to address limitations in MSC gene therapy, while viral vectors may pose risks.
Article
Biochemistry & Molecular Biology
Vyacheslav Chernykh, Stanislav Krasovsky, Olga Solovova, Tagui Adyan, Anna Stepanova, Ekaterina Marnat, Maria Shtaut, Anna Sedova, Tatyana Sorokina, Tatyana Beskorovainaya, Elena Kondratyeva, Olga Shchagina, Aleksandr Polyakov
Summary: There are differences in the frequency of CFTR variants and genotypes between Russian CF and CBAVD patients.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Evelina Moliteo, Monica Sciacca, Antonino Palmeri, Maria Papale, Sara Manti, Giuseppe Fabio Parisi, Salvatore Leonardi
Summary: There is substantial evidence that patients with cystic fibrosis (CF) have higher oxidative stress levels, which contribute to the progression of chronic lung damage. CF patients exhibit an abnormal proinflammatory environment in their airways even before infection, possibly due to elevated oxidative stress and abnormal lipid metabolism. CFTR deficiency appears to cause a redox imbalance in epithelial cells and extracellular fluids.
Review
Immunology
Buqing Yi, Alexander H. Dalpke, Sebastien Boutin
Summary: The development of CFTR modulator therapies has significantly changed the treatment scheme of people with cystic fibrosis, but further research is needed to understand the effects of such modulation on the airway microbiome for managing airway infections effectively.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2021)
Review
Genetics & Heredity
Svetlana A. Smirnikhina
Summary: This article examines the current status and challenges of gene therapy for cystic fibrosis, and suggests that the emergence of genome editing methods offers new possibilities for overcoming the limitations of traditional approaches.
CURRENT GENE THERAPY
(2022)
Review
Cell & Tissue Engineering
Pinyan Liu, Yongcui Mao, Ye Xie, Jiayun Wei, Jia Yao
Summary: This review summarizes the published clinical trials of stem cells for the treatment of liver fibrosis/cirrhosis and provides an overview of various cell sources, cell doses, and delivery methods. The molecular mechanisms of how stem cells play a therapeutic role in liver fibrosis and the prospects of future clinical implementation of stem cells are also discussed.
STEM CELL RESEARCH & THERAPY
(2022)
Article
Multidisciplinary Sciences
Sharon L. Wong, Nikhil T. Awatade, Miro A. Astore, Katelin M. Allan, Michael J. Carnell, Iveta Slapetova, Po-chia Chen, Alexander Capraro, Laura K. Fawcett, Renee M. Whan, Renate Griffith, Chee Y. Ooi, Serdar Kuyucak, Adam Jaffe, Shafagh A. Waters
Summary: In this study, the characterization of the I37R mutation in the lasso motif of the CFTR chloride channel was conducted. It was found that the I37R-CFTR mutation results in a residual function defect that can be treated with potentiators and type III correctors. This study provides insights into CFTR channel regulation and offers a potential pathway for drug access in CF patients with ultra-rare genotypes.
Article
Biochemistry & Molecular Biology
Sharon L. Wong, Nikhil T. Awatade, Miro A. Astore, Katelin M. Allan, Michael J. Carnell, Iveta Slapetova, Po-Chia Chen, Jeffry Setiadi, Elvis Pandzic, Laura K. Fawcett, John R. Widger, Renee M. Whan, Renate Griffith, Chee Y. Ooi, Serdar Kuyucak, Adam Jaffe, Shafagh A. Waters
Summary: This study investigated the structural and functional defects of the rare CFTR mutation R352Q in cell models of the airway and gut. The mutation showed residual CFTR function, which could be restored by CFTR potentiators but not the corrector. Molecular dynamics simulations indicated a chloride conductance defect rather than a gating defect. The combination of in vitro patient-derived cell models and in silico simulations can improve predictions of modulator response and aid in CF precision medicine.
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Alexandra McCarron, Patricia Cmielewski, Victoria Drysdale, David Parsons, Martin Donnelley
Summary: This article reviews the challenges of gene-based therapeutics for lung diseases. Various barriers in the lung limit the efficacy of gene transfer. Airway surface preparation methods have been developed to disrupt these barriers and create a more favorable environment for gene delivery. However, these methods have not been clinically utilized.
Article
Health Care Sciences & Services
Sharon L. Wong, Elvis Pandzic, Egi Kardia, Katelin M. Allan, Renee M. Whan, Shafagh A. Waters
Summary: Infection control and antibiotic therapy are crucial for managing airway infections in patients with cystic fibrosis. The use of airway epithelial cell cultures grown at air-liquid interface (ALI) provides a physiologically relevant model for studying respiratory infections. Immunofluorescence staining and imaging are effective tools for understanding host-pathogen interactions and exploring potential treatments. A quantitative fluorescence microscopy assay using a graphical user interface (GUI) package is described for identifying specific cell populations and pathogen targets in ALI cultures.
JOURNAL OF PERSONALIZED MEDICINE
(2022)
Article
Biotechnology & Applied Microbiology
Martin Donnelley, David Parsons, Ivanka Prichard
Summary: The studies indicate that people with CF, their families, and the general public have positive perceptions towards airway gene therapy and are supportive of participating in CF gene therapy trials. The majority hope that gene therapy can provide a cure and believe it is still necessary even with improvements from current medications.
EXPERT OPINION ON BIOLOGICAL THERAPY
(2023)
Article
Pediatrics
Katelin M. Allan, Miro A. Astore, Laura K. Fawcett, Sharon L. Wong, Po-Chia Chen, Renate Griffith, Adam Jaffe, Serdar Kuyucak, Shafagh A. Waters
Summary: Cystic Fibrosis (CF) is caused by mutations in the CFTR gene, and targeted therapies have been developed to restore the function of CFTR protein. This study demonstrated in vitro and in vivo that a combination of modulators can effectively address the folding and gating defects of CFTR.
FRONTIERS IN PEDIATRICS
(2022)
Article
Biochemistry & Molecular Biology
Martin Donnelley, Patricia Cmielewski, Emma Knight, Chantelle Carpentieri, Alexandra McCarron, Nathan Rout-Pitt, David Parsons, Nigel Farrow
Summary: The study aimed to determine if repeat dosing of a VSV-G pseudotyped LV vector is more effective than a single dose in increasing gene expression in mouse lungs. Over a 12-month period, most dosing schedules produced detectable bioluminescence, with shorter intervals (<= 1 wk) resulting in higher flux levels compared to longer intervals (at least 1 month, five doses). Ex vivo lung analysis at 12 months showed that the group receiving two doses 1 week apart had significantly higher luciferase expression compared to the single dose group and the groups with doses over a period greater than 1 week.
Article
Biochemistry & Molecular Biology
Nirajan Shrestha, Nathan Rout-Pitt, Alexandra McCarron, Courtney A. A. Jackson, Andrew C. C. Bulmer, Andrew J. J. McAinch, Martin Donnelley, David W. W. Parsons, Deanne H. H. Hryciw
Summary: This study aimed to investigate the characteristics of essential fatty acid deficiency caused by cystic fibrosis (CF), which is the result of mutations in the CF transmembrane conductance regulator (CFTR). Two rodent models of CF were studied: one strain with a loss of phenylalanine at position 508 (Phe508del) in CFTR and the other lacking functional CFTR (510X). Fatty acid concentrations were measured in the serum, and the expression of genes related to fatty acid transport and metabolism was quantified. Histological assessment of the ileal tissue was also performed. The results showed genotype- and age-dependent alterations in fatty acid concentration, as well as changes in gene expression and tissue morphology. These findings suggest that CF rat models exhibit abnormalities in the handling of fatty acids, possibly due to altered transport and metabolism, as well as fibrosis and structural changes in the ileum.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Sharon L. Wong, Egi Kardia, Abhishek Vijayan, Bala Umashankar, Elvis Pandzic, Ling Zhong, Adam Jaffe, Shafagh A. Waters
Summary: Localized and chronic hypoxia affects the function and structure of airway stem cells and differentiated epithelium in individuals with cystic fibrosis (CF). The study investigated the impact of chronic hypoxia on nasal epithelial cells (hNECs) derived from CF and non-CF individuals. The results showed that chronic hypoxia led to alterations in morphology, global proteomics, and function of hNECs, including reduced barrier integrity and modulation of cilia motility and ion transport. The activity of epithelial sodium and CFTR ion channels was reduced under chronic hypoxia, affecting the response to CFTR-targeted therapies.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Thomas G. Molley, Shouyuan Jiang, Louis Ong, Chantal Kopecky, Chavinya D. Ranaweera, Gagan K. Jalandhra, Laura Milton, Egi Kardia, Zeheng Zhou, Jelena Rnjak-Kovacina, Shafagh A. Waters, Yi-Chin Toh, Kristopher A. Kilian Abh
Summary: This work developed a high-loading enzyme encapsulation approach that precisely controls the oxygen content in cell culture, demonstrating its application in various cells and promoting neovascularization. This platform's simplicity and flexibility make it useful for studying oxygen-mediated processes in any in vitro or in vivo format.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Review
Physiology
Nicole Reyne, Alexandra McCarron, Patricia Cmielewski, David Parsons, Martin Donnelley
Summary: Cystic fibrosis lung disease is caused by recurrent bacterial infections, particularly Pseudomonas aeruginosa. Current animal models do not fully replicate the human disease, including environmental pathogen colonization. Delivering bacteria in different forms to the lungs of animals can model cystic fibrosis bacterial lung infections. Developing more accurate lung infection models has the potential to advance understanding and treatment of cystic fibrosis lung disease.
FRONTIERS IN PHYSIOLOGY
(2023)
Article
Health Care Sciences & Services
Laura K. Fawcett, Nihan Turgutoglu, Katelin M. Allan, Yvonne Belessis, John Widger, Adam Jaffe, Shafagh A. Waters
Summary: Primary nasal epithelial cells and culture models are essential tools for diagnosing, researching and developing drugs for airway diseases. This study compared two cytology brushes, Olympus and Endoscan, in collecting nasal epithelial cells. Results showed that the choice of brush did not affect diagnostic accuracy, but the Endoscan brush was more efficient in collecting total and live cells. Furthermore, the Endoscan brush was more cost-effective compared to the Olympus brush.
JOURNAL OF PERSONALIZED MEDICINE
(2023)
Meeting Abstract
Biotechnology & Applied Microbiology
Martin Donnelley, Patricia Cmielewski, Kaye Morgan, Juliette Delhove, Nikki Reyne, Alexandra McCarron, Victoria Drysdale, Chantelle Carpentieri, Kathryn Spiers, Akihisa Takeuchi, Kentaro Uesugi, Naoto Yagi, David Parsons
Meeting Abstract
Biotechnology & Applied Microbiology
Victoria Drysdale, Patricia Cmielewski, Martin Donnelley, David Parsons, Nicole Reyne, Alexandra McCarron