Cell-Based Therapeutic Approaches for Cystic Fibrosis

Duchesneau, Pascal; Waddell, Thomas K.; Karoubi, Golnaz

doi:10.3390/ijms21155219

Cited by 14 publications

(17 citation statements)

References 161 publications

(228 reference statements)

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“…Whole bone marrow aspirates, hMSC and Cftr sufficient macrophages provide clear implications for therapeutic development of immune support in managing CF lung infection and inflammation based upon the data we have presented in this manuscript. These observations are consistent with previous studies that have also pursued immune supportive therapeutic directives ( Weiss, 2008 ; Bruscia et al, 2009 ; Bonfield et al, 2012 ; Sutton et al, 2017 ; Duchesneau et al, 2020 ; Zhang et al, 2020 ). Follow-up studies will focus on delivering CF macrophages or hMSCs in the preclinical model and further investigate the functional insufficiency of CF derived cells.…”

Section: Discussionsupporting

confidence: 92%

Enhancing Cystic Fibrosis Immune Regulation

et al. 2021

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In cystic fibrosis (CF), sustained infection and exuberant inflammation results in debilitating and often fatal lung disease. Advancement in CF therapeutics has provided successful treatment regimens for a variety of clinical consequences in CF; however effective means to treat the pulmonary infection and inflammation continues to be problematic. Even with the successful development of small molecule cystic fibrosis transmembrane conductance regulator (CFTR) correctors and potentiators, there is only a modest effect on established infection and inflammation in CF patients. In the pursuit of therapeutics to treat inflammation, the conundrum to address is how to overcome the inflammatory response without jeopardizing the required immunity to manage pathogens and prevent infection. The key therapeutic would have the capacity to dull the inflammatory response, while sustaining the ability to manage infections. Advances in cell-based therapy have opened up the avenue for dynamic and versatile immune interventions that may support this requirement. Cell based therapy has the capacity to augment the patient’s own ability to manage their inflammatory status while at the same time sustaining anti-pathogen immunity. The studies highlighted in this manuscript outline the potential use of cell-based therapy for CF. The data demonstrate that 1) total bone marrow aspirates containing Cftr sufficient hematopoietic and mesenchymal stem cells (hMSCs) provide Cftr deficient mice >50% improvement in survival and improved management of infection and inflammation; 2) myeloid cells can provide sufficient Cftr to provide pre-clinical anti-inflammatory and antimicrobial benefit; 3) hMSCs provide significant improvement in survival and management of infection and inflammation in CF; 4) the combined interaction between macrophages and hMSCs can potentially enhance anti-inflammatory and antimicrobial support through manipulating PPARγ. These data support the development of optimized cell-based therapeutics to enhance CF patient’s own immune repertoire and capacity to maintain the balance between inflammation and pathogen management.

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Section: Discussionsupporting

confidence: 92%

Enhancing Cystic Fibrosis Immune Regulation

et al. 2021

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“…[9,365] Even though CF affects the epithelial secretory balance of other organs, such as the intestine, liver, pancreas, and gallbladder, its manifestation in the lungs is the principal factor driving high morbidity and mortality rates. [366] There is a vast heterogeneity in the disease phenotype manifested among patients carrying similar mutant CFTR variants, revealing an ambiguous genotype-phenotype relationship that can be influenced by modifier genes and environmental factors. [365,367] The amenability for genetic manipulation of iPSCs allows, in principle, to isolate and reprogram somatic cells from CF patients back to pluripotency, analyze their respective genotype and identify individual CFTR mutant variants, and, applying advanced gene editing technology, correct such mutations, recovering CFTR protein function.…”

Section: Pulmonary Fibrotic Diseasesmentioning

confidence: 99%

Advanced In Vitro Lung Models for Drug and Toxicity Screening: The Promising Role of Induced Pluripotent Stem Cells

Moreira¹,

Müller

Costa³

et al. 2021

Advanced Biology

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Respiratory diseases are among the global leading causes of morbidity and mortality. Acute conditions arising from infection, such as pneumonia and tuberculosis, affect millions of people worldwide, the latter being the most common lethal infectious disease with 1.4 million annual deaths. [1] Upon infection, the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), which caused a worldwide pandemic, leads to the clinical picture of the coronavirus disease-2019 (COVID-19) with possibly severe and life-threatening progression. Lung cancer is the most frequently diagnosed malignancy and the main cause of cancer-related death, [2] with markedly low survival rates especially when the diagnosis is performed at an advanced state of the disease. [3] Moreover, chronic respiratory diseases (CRDs), including chronic obstructive pulmonary disease (COPD), asthma, and interstitial lung disease (ILD), have consistently received less attention in comparison to other non-communicable diseases, continuing to exert a considerable socioeconomic impact. [4,5] Risk factors for the development of respiratory diseases include, for example, tobacco use and second-hand smoke, as well as exposure to air-pollutants, which has been accentuated with the widespread use of fossil fuels. [4] It is clear that a great number of these risks can be mitigated by lifestyle changes, promoted by anti-tobacco campaigns already in place at a global scale and by the use of renewable, clean energy sources, and two recent studies indicate that the age-standardized incidence and prevalence of CRDs has decreased from 1990 to 2017. [4,5] However, the risk of developing CRDs, particularly COPD, appears to increase steeply with age; [4,5] most strikingly, these diseases were the third leading cause of death in 2017 [4] and potentially in 2020. [6] In addition to microbial, environmental, and lifestyle-related factors, a large number of lung diseases have a genetic origin. [7] Cystic fibrosis (CF), for example, is an incurable hereditary disorder known to originate from different mutations in the gene coding for the CF transmembrane conductance regulator (CFTR), an ion transporter, resulting in severe alterations in pulmonary physiology that culminate in impaired lung function, respiratory distress and, ultimately, death. [8,9]

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“…The application of theranostics in CF includes targeted cell delivery, nanoparticle-based contrast agents for imaging, real-time assessment of CFTR-therapeutics and lung function, and predicting or tracking exacerbations. Theranostics may target epithelial and inflammatory cells in vivo, as we recently described [ 38 , 78 , 79 , 80 , 81 ], or utilize ex vivo patient samples or stem cells as cell therapy or biologics [ 82 , 83 , 84 , 85 ].…”

Section: Perspectivementioning

confidence: 99%

Prognosis-Based Early Intervention Strategies to Resolve Exacerbation and Progressive Lung Function Decline in Cystic Fibrosis

Vij

2021

JPM

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Cystic fibrosis (CF) is a genetic disease caused by a mutation(s) in the CF transmembrane regulator (CFTR), where progressive decline in lung function due to recurring exacerbations is a major cause of mortality. The initiation of chronic obstructive lung disease in CF involves inflammation and exacerbations, leading to mucus obstruction and lung function decline. Even though clinical management of CF lung disease has prolonged survival, exacerbation and age-related lung function decline remain a challenge for controlling the progressive lung disease. The key to the resolution of progressive lung disease is prognosis-based early therapeutic intervention; thus, the development of novel diagnostics and prognostic biomarkers for predicting exacerbation and lung function decline will allow optimal management of the lung disease. Hence, the development of real-time lung function diagnostics such as forced oscillation technique (FOT), impulse oscillometry system (IOS), and electrical impedance tomography (EIT), and novel prognosis-based intervention strategies for controlling the progression of chronic obstructive lung disease will fulfill a significant unmet need for CF patients. Early detection of CF lung inflammation and exacerbations with the timely resolution will not only prolong survival and reduce mortality but also improve quality of life while reducing significant health care costs due to recurring hospitalizations.

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Cell-Based Therapeutic Approaches for Cystic Fibrosis

Cited by 14 publications

References 161 publications

Enhancing Cystic Fibrosis Immune Regulation

Enhancing Cystic Fibrosis Immune Regulation

Advanced In Vitro Lung Models for Drug and Toxicity Screening: The Promising Role of Induced Pluripotent Stem Cells

Prognosis-Based Early Intervention Strategies to Resolve Exacerbation and Progressive Lung Function Decline in Cystic Fibrosis

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