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Full-Text Articles in Medicine and Health Sciences
Functional Characterization Of A Recombinant Adeno-Associated Virus 5-Pseudotyped Cystic Fibrosis Transmembrane Conductance Regulator Vector, Jeffrey Sirninger, Christian Mueller, Sofia Braag, Qiushi Tang, Hungwen Yue, Carol Detrisac, Thomas Ferkol, William Guggino, Terence Flotte
Functional Characterization Of A Recombinant Adeno-Associated Virus 5-Pseudotyped Cystic Fibrosis Transmembrane Conductance Regulator Vector, Jeffrey Sirninger, Christian Mueller, Sofia Braag, Qiushi Tang, Hungwen Yue, Carol Detrisac, Thomas Ferkol, William Guggino, Terence Flotte
Christian Mueller
Despite extensive experience with recombinant adeno-associated virus (rAAV) 2 vectors in the lung, gene expression has been low in the context of cystic fibrosis (CF) gene therapy, where the large size of the cystic fibrosis transmembrane conductance regulator (CFTR) coding sequence has prompted the use of compact endogenous promoter elements. We evaluated the possibility that gene expression from recombinant adeno-associated virus (rAAV) could be improved by using alternate AAV capsid serotypes that target different cell-surface receptors (i.e., rAAV5) and/or using stronger promoters. The relative activities of the cytomegalovirus (CMV) Rous sarcoma virus (RSV) promoter, the CMV enhancer/beta-actin (CB) promoter combination, …
Cystic Fibrosis Transmembrane Conductance Regulator Deficiency Exacerbates Islet Cell Dysfunction After Beta-Cell Injury, Michael Stalvey, Christian Mueller, Desmond Schatz, Clive Wasserfall, Martha Campbell-Thompson, Douglas Theriaque, Terence Flotte, Mark Atkinson
Cystic Fibrosis Transmembrane Conductance Regulator Deficiency Exacerbates Islet Cell Dysfunction After Beta-Cell Injury, Michael Stalvey, Christian Mueller, Desmond Schatz, Clive Wasserfall, Martha Campbell-Thompson, Douglas Theriaque, Terence Flotte, Mark Atkinson
Christian Mueller
The cause of cystic fibrosis-related diabetes (CFRD) remains unknown, but cystic fibrosis transmembrane conductance regulator (CFTR) mutations contribute directly to multiple aspects of the cystic fibrosis phenotype. We hypothesized that susceptibility to islet dysfunction in cystic fibrosis is determined by the lack of functional CFTR. To address this, glycemia was assessed in CFTR null (CFTR(-/-)), C57BL/6J, and FVB/NJ mice after streptozotocin (STZ)-induced beta-cell injury. Fasting blood glucose levels were similar among age-matched non-STZ-administered animals, but they were significantly higher in CFTR(-/-) mice 4 weeks after STZ administration (288.4 +/- 97.4, 168.4 +/- 35.9, and 188.0 +/- 42.3 mg/dl for CFTR(-/-), …
Enhanced Ige Allergic Response To Aspergillus Fumigatus In Cftr-/- Mice, Christian Mueller, Sofia Braag, John-David Herlihy, Clive Wasserfall, Sarah Chesrown, Harry Nick, Mark Atkinson, Terence Flotte
Enhanced Ige Allergic Response To Aspergillus Fumigatus In Cftr-/- Mice, Christian Mueller, Sofia Braag, John-David Herlihy, Clive Wasserfall, Sarah Chesrown, Harry Nick, Mark Atkinson, Terence Flotte
Christian Mueller
To gain insight into aberrant cytokine regulation in cystic fibrosis (CF), we compared the phenotypic manifestations of allergen challenge in gut-corrected CFTR-deficient mice with background-matched C57Bl6 (B6) mice. Aspergillus fumigatus (Af) antigen was used to mimic allergic bronchopulmonary aspergillosis, a peculiar hyper-IgE syndrome with a high prevalence in CF patients. CFTR-/-, C57BL/6 and FVB/NJ mice were sensitized with Af antigen by serial intraperitoneal injections. Control mice were mock sensitized with PBS. Challenges were performed by inhalation of Af antigen aerosol. After Af antigen challenge, histologic analysis showed goblet cell hyperplasia and lymphocytic infiltration in both strains. However, total serum IgE …
Cystic Fibrosis, Michael Stalvey, Christian Mueller, Terence Flotte
Cystic Fibrosis, Michael Stalvey, Christian Mueller, Terence Flotte
Christian Mueller
Citation: Stalvey, M., Mueller, C., and Flotte, T. “Cystic Fibrosis”, in Domino FJ, ed., The 5-Minute Clinical Consult 2011. Lippincott Williams & Wilkins, 19th Edition, p. 340-341, 2010. A preview of this chapter is available via Google Books.
Cftr Mutations Impart Elevated Immune Reactivity In A Murine Model Of Cystic Fibrosis Related Diabetes, Michael Stalvey, Todd Brusko, Christian Mueller, Clive Wasserfall, Desmond Schatz, Mark Atkinson, Terence Flotte
Cftr Mutations Impart Elevated Immune Reactivity In A Murine Model Of Cystic Fibrosis Related Diabetes, Michael Stalvey, Todd Brusko, Christian Mueller, Clive Wasserfall, Desmond Schatz, Mark Atkinson, Terence Flotte
Christian Mueller
Increased life expectancy in cystic fibrosis (CF) is accompanied by an increasing incidence of CF related diabetes (CFRD). Altered immune reactivity occurs in CF, which we hypothesize, is exacerbated by hyperglycemia. Cystic fibrosis transmembrane conductance regulator deficient (CFTR-/-) mice were rendered hyperglycemic by streptozotocin (STZ) to test this hypothesis. CFTR-/-, C57BL/6J, and FVB/NJ mice received either STZ or lactated ringers (LR) (n=5-10). Four weeks later, splenocytes were harvested, mitogen stimulated, and analyzed for cytokine production (IL-2, IL-4, and IL-10) along with stimulation indices (SI). SI of STZ-treated CFTR-/- were elevated compared to LR-treated mice, although both were greater than C57BL/6J …
The Pros And Cons Of Immunomodulatory Il-10 Gene Therapy With Recombinant Aav In A Cftr-/- -Dependent Allergy Mouse Model, Christian Mueller, Sofia Braag, A. Martino, Qiushi Tang, M. Campbell-Thompson, Terence Flotte
The Pros And Cons Of Immunomodulatory Il-10 Gene Therapy With Recombinant Aav In A Cftr-/- -Dependent Allergy Mouse Model, Christian Mueller, Sofia Braag, A. Martino, Qiushi Tang, M. Campbell-Thompson, Terence Flotte
Christian Mueller
Cystic fibrosis (CF) patients have decreased levels of lung epithelial interleukin (IL)-10 and increased levels of proinflammatory cytokines (tumor necrosis factor-alpha, IL-4, IL-8 and IL-6). This has also been documented in Cftr (cystic fibrosis transmembrane conductance regulator)-deficient mice (Cftr 489X(-/-), FABP-hCFTR(+/+)). Our laboratory has recently characterized a peculiar hyper-IgE phenotype in these mice, in response to Aspergillus fumigatus crude protein extract (Af-cpe). Thus, we hypothesized that sustained systemic circulating IL-10 levels achieved through skeletal muscle transduction with recombinant adeno-associated vectors expressing IL-10 (rAAV1-IL-10) would serve to downregulate Th1 and Th2 cytokine production. This in turn would dampen the allergic response …
Induction Of Group Ivc Phospholipase A2 In Allergic Asthma: Transcriptional Regulation By Tnf-Α In Bronchoepithelial Cells, Justin S. Bickford, Kimberly J. Newsom, John-David Herlihy, Christian Mueller, Benjamin Keeler, Xiaolei Qiu, Jewell N. Walters, Nan Su, Shannon M. Wallet, Terence R. Flotte, Harry S. Nick
Induction Of Group Ivc Phospholipase A2 In Allergic Asthma: Transcriptional Regulation By Tnf-Α In Bronchoepithelial Cells, Justin S. Bickford, Kimberly J. Newsom, John-David Herlihy, Christian Mueller, Benjamin Keeler, Xiaolei Qiu, Jewell N. Walters, Nan Su, Shannon M. Wallet, Terence R. Flotte, Harry S. Nick
Christian Mueller
Airway inflammation in allergen-induced asthma is associated with eicosanoid release. These bioactive lipids exhibit anti- and pro-inflammatory activities with relevance to pulmonary pathophysiology. We hypothesized that sensitization/challenge using an extract from the ubiquitous fungus, Aspergillus fumigatus (Af), in a mouse model of allergic asthma would result in altered phospholipase gene expression, thus modulating the downstream eicosanoid pathway. We observed the most significant induction in the group IVC phospholipase A2 (cPLA2γ or PLA2G4C). Our results infer that Af extract can induce cPLA2γ levels directly in eosinophils while induction in lung epithelial cells is most likely a consequence of TNF-α secretion by …
N-Glycosylation Augmentation Of The Cystic Fibrosis Epithelium Improves Pseudomonas Aeruginosa Clearance, Ashley Martino, Christian Mueller, Sofia Braag, Pedro Cruz, Martha Campbell-Thompson, Shouguang Jin, Terence Flotte
N-Glycosylation Augmentation Of The Cystic Fibrosis Epithelium Improves Pseudomonas Aeruginosa Clearance, Ashley Martino, Christian Mueller, Sofia Braag, Pedro Cruz, Martha Campbell-Thompson, Shouguang Jin, Terence Flotte
Christian Mueller
Chronic lung colonization with Pseudomonas aeruginosa is anticipated in cystic fibrosis (CF). Abnormal terminal glycosylation has been implicated as a candidate for this condition. We previously reported a down-regulation of mannose-6-phosphate isomerase (MPI) for core N-glycan production in the CFTR-defective human cell line (IB3). We found a 40% decrease in N-glycosylation of IB3 cells compared with CFTR-corrected human cell line (S9), along with a threefold-lower surface attachment of P. aeruginosa strain, PAO1. There was a twofold increase in intracellular bacteria in S9 cells compared with IB3 cells. After a 4-hour clearance period, intracellular bacteria in IB3 cells increased twofold. Comparatively, …
In Vitro And In Vivo Functional Characterization Of Gutless Recombinant Sv40-Derived Cftr Vectors, Christian Mueller, M. Strayer, Jeffrey Sirninger, Sofia Braag, Francisco Branco, Jean-Pierre Louboutin, Terence Flotte, David Strayer
In Vitro And In Vivo Functional Characterization Of Gutless Recombinant Sv40-Derived Cftr Vectors, Christian Mueller, M. Strayer, Jeffrey Sirninger, Sofia Braag, Francisco Branco, Jean-Pierre Louboutin, Terence Flotte, David Strayer
Christian Mueller
In cystic fibrosis (CF), respiratory failure caused by progressive airway obstruction and tissue damage is primarily a result of the aberrant inflammatory responses to lung infections with Pseudomonas aeruginosa. Despite considerable improvement in patient survival, conventional therapies are mainly supportive. Recent progress toward gene therapy for CF has been encouraging; however, several factors such as immune response and transduced cell turnover remain as potential limitations to CF gene therapy. As alternative gene therapy vectors for CF, we examined the feasibility of using recombinant SV40-derived vectors (rSV40s), which may circumvent some of these obstacles. To accommodate the large cystic fibrosis transmembrane …
Dual Reporter Comparative Indexing Of Raav Pseudotyped Vectors In Chimpanzee Airway, Terence Flotte, Anne Fischer, Jason Goetzmann, Christian Mueller, Liudmila Cebotaru, Ziying Yan, Lilli Wang, James Wilson, William Guggino, John Engelhardt
Dual Reporter Comparative Indexing Of Raav Pseudotyped Vectors In Chimpanzee Airway, Terence Flotte, Anne Fischer, Jason Goetzmann, Christian Mueller, Liudmila Cebotaru, Ziying Yan, Lilli Wang, James Wilson, William Guggino, John Engelhardt
Christian Mueller
Selecting the most efficient recombinant adeno-associated virus (rAAV) serotype for airway gene therapy has been difficult due to cross-specific differences in tropism and immune response between humans and animal models. Chimpanzees--the closest surviving genetic relative of humans--provide a valuable opportunity to select the most effective serotypes for clinical trials in humans. However, designing informative experiments using this protected species is challenging due to limited availability and experimental regulations. We have developed a method using Renilla luciferase (RL) and firefly luciferase (FL) reporters to directly index the relative transduction and immune response of two promising rAAV serotypes following lung coinfection. Analysis …
Gene Therapy For Cystic Fibrosis, Christian Mueller, Terence Flotte
Gene Therapy For Cystic Fibrosis, Christian Mueller, Terence Flotte
Christian Mueller
Cystic Fibrosis (CF) is an autosomal recessive disorder due to mutations in the CF transmembrane conductance regulator (CFTR) gene that lead to defective ion transport in the conducting pulmonary airways and exocrine glands. Through a process that is not fully understood, CFTR defects predispose affected patients to chronic endobronchial infections with organisms such as Pseudomonas aeruginosa and Staphylococcus aureus. Following the discovery of the CFTR gene in 1989, CF became one of the primary targets for gene therapy research. Early enthusiasm surrounded the new field of gene therapy during most of the 1990s and it led academics and clinicians on …