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Full-Text Articles in Life Sciences
Central Role Of Il-23 And Il-17 Producing Eosinophils As Immunomodulatory Effector Cells In Acute Pulmonary Aspergillosis And Allergic Asthma, Evelyn V. Santos Guerra, Chrono K. Lee, Charles A. Specht, Bhawna Yadav, Haibin Huang, Ali Akalin, Jun R. Huh, Christian Mueller, Stuart M. Levitz
Central Role Of Il-23 And Il-17 Producing Eosinophils As Immunomodulatory Effector Cells In Acute Pulmonary Aspergillosis And Allergic Asthma, Evelyn V. Santos Guerra, Chrono K. Lee, Charles A. Specht, Bhawna Yadav, Haibin Huang, Ali Akalin, Jun R. Huh, Christian Mueller, Stuart M. Levitz
Christian Mueller
Aspergillus fumigatus causes invasive pulmonary disease in immunocompromised hosts and allergic asthma in atopic individuals. We studied the contribution of lung eosinophils to these fungal diseases. By in vivo intracellular cytokine staining and confocal microscopy, we observed that eosinophils act as local sources of IL-23 and IL-17. Remarkably, mice lacking eosinophils had a >95% reduction in the percentage of lung IL-23p19+ cells as well as markedly reduced IL-23 heterodimer in lung lavage fluid. Eosinophils killed A. fumigatus conidia in vivo. Eosinopenic mice had higher mortality rates, decreased recruitment of inflammatory monocytes, and decreased expansion of lung macrophages after challenge with …
Recombinant Aav Serotype And Capsid Mutant Comparison For Pulmonary Gene Transfer Of Alpha-1-Antitrypsin Using Invasive And Noninvasive Delivery, Rejean Liqun Wang, Thomas J. Mclaughlin, Travis Cossette, Qiushi Tang, Kevin Foust, Martha Campbell-Thompson, Ashley Martino, Pedro Cruz, Scott Loiler, Christian Mueller, Terence R. Flotte
Recombinant Aav Serotype And Capsid Mutant Comparison For Pulmonary Gene Transfer Of Alpha-1-Antitrypsin Using Invasive And Noninvasive Delivery, Rejean Liqun Wang, Thomas J. Mclaughlin, Travis Cossette, Qiushi Tang, Kevin Foust, Martha Campbell-Thompson, Ashley Martino, Pedro Cruz, Scott Loiler, Christian Mueller, Terence R. Flotte
Christian Mueller
Recombinant adeno-associated viral (rAAV) vectors have been widely used in pulmonary gene therapy research. In this study, we evaluated the transduction and expression efficiencies of several AAV serotypes and AAV2 capsid mutants with specific pulmonary targeting ligands in the mouse lung. The noninvasive intranasal delivery was compared with the traditional intratracheal lung delivery. The rAAV8 was the most efficient serotype at expressing alpha-1-antitrypsin (AAT) in the lung among all the tested serotypes and mutants. A dose of 1 x 1010 vg of rAAV8-CB-AAT transduced a high percentage of cells in the lung when delivered intratrachealy. The serum and the broncho-alveolar …
Self-Complementary Adeno-Associated Virus Vectors Improve Transduction Efficiency Of Corneal Endothelial Cells, Anja K. Gruenert, Marta Czugala, Christian Mueller, Marco Schmeer, Martin Schleef, Friedrich E. Kruse, Thomas A. Fuchsluger
Self-Complementary Adeno-Associated Virus Vectors Improve Transduction Efficiency Of Corneal Endothelial Cells, Anja K. Gruenert, Marta Czugala, Christian Mueller, Marco Schmeer, Martin Schleef, Friedrich E. Kruse, Thomas A. Fuchsluger
Christian Mueller
Transplantation of a donor cornea to restore vision is the most frequently performed transplantation in the world. Corneal endothelial cells (CEC) are crucial for the outcome of a graft as they maintain corneal transparency and avoid graft failure due to corneal opaqueness. Given the characteristic of being a monolayer and in direct contact with culture medium during cultivation in eye banks, CEC are specifically suitable for gene therapeutic approaches prior to transplantation. Recombinant adeno-associated virus 2 (rAAV2) vectors represent a promising tool for gene therapy of CEC. However, high vector titers are needed to achieve sufficient gene expression. One of …
Targeted Gene Delivery To The Enteric Nervous System Using Aav: A Comparison Across Serotypes And Capsid Mutants, Matthew J. Benskey, Nathan C. Kuhn, James J. Galligan, Joanna Garcia, Shannon E. Boye, William W. Hauswirth, Christian Mueller, Sanford L. Boye, Fredric P. Manfredsson
Targeted Gene Delivery To The Enteric Nervous System Using Aav: A Comparison Across Serotypes And Capsid Mutants, Matthew J. Benskey, Nathan C. Kuhn, James J. Galligan, Joanna Garcia, Shannon E. Boye, William W. Hauswirth, Christian Mueller, Sanford L. Boye, Fredric P. Manfredsson
Christian Mueller
Recombinant adeno-associated virus (AAV) vectors are one of the most widely used gene transfer systems in research and clinical trials. AAV can transduce a wide range of biological tissues, however to date, there has been no investigation on targeted AAV transduction of the enteric nervous system (ENS). Here, we examined the efficiency, tropism, spread, and immunogenicity of AAV transduction in the ENS. Rats received direct injections of various AAV serotypes expressing green fluorescent protein (GFP) into the descending colon. AAV serotypes tested included; AAV 1, 2, 5, 6, 8, or 9 and the AAV2 and AAV8 capsid mutants, AAV2-Y444F, AAV2-tripleY-F, …
Phase 2 Clinical Trial Of A Recombinant Adeno-Associated Viral Vector Expressing Α1-Antitrypsin: Interim Results, Terence R. Flotte, Bruce C. Trapnell, Margaret Humphries, Brenna Carey, Roberto Calcedo, Farshid Rouhani, Martha Campbell-Thompson, Anthony T. Yachnis, Robert A. Sandhaus, Noel G. Mcelvaney, Christian Mueller, Louis M. Messina, James M. Wilson, Mark L. Brantly, David R. Knop, Guo-Jie Ye, Jeffrey D. Chulay
Phase 2 Clinical Trial Of A Recombinant Adeno-Associated Viral Vector Expressing Α1-Antitrypsin: Interim Results, Terence R. Flotte, Bruce C. Trapnell, Margaret Humphries, Brenna Carey, Roberto Calcedo, Farshid Rouhani, Martha Campbell-Thompson, Anthony T. Yachnis, Robert A. Sandhaus, Noel G. Mcelvaney, Christian Mueller, Louis M. Messina, James M. Wilson, Mark L. Brantly, David R. Knop, Guo-Jie Ye, Jeffrey D. Chulay
Christian Mueller
Recombinant adeno-associated virus (rAAV) vectors offer promise for the gene therapy of α(1)-antitrypsin (AAT) deficiency. In our prior trial, an rAAV vector expressing human AAT (rAAV1-CB-hAAT) provided sustained, vector-derived AAT expression for >1 year. In the current phase 2 clinical trial, this same vector, produced by a herpes simplex virus complementation method, was administered to nine AAT-deficient individuals by intramuscular injection at doses of 6.0×10(11), 1.9×10(12), and 6.0×10(12) vector genomes/kg (n=3 subjects/dose). Vector-derived expression of normal (M-type) AAT in serum was dose dependent, peaked on day 30, and persisted for at least 90 days. Vector administration was well tolerated, with …
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 …
Sustained Transgene Expression Despite T Lymphocyte Responses In A Clinical Trial Of Raav1-Aat Gene Therapy, Mark L. Brantly, Jeffrey D. Chulay, Lili Wang, Christian Mueller, Margaret Humphries, L. Terry Spencer, Farshid Rouhani, Thomas J. Conlon, Roberto Calcedo, Michael R. Betts, Carolyn Spencer, Barry J. Bryne, James M. Wilson, Terence R. Flotte
Sustained Transgene Expression Despite T Lymphocyte Responses In A Clinical Trial Of Raav1-Aat Gene Therapy, Mark L. Brantly, Jeffrey D. Chulay, Lili Wang, Christian Mueller, Margaret Humphries, L. Terry Spencer, Farshid Rouhani, Thomas J. Conlon, Roberto Calcedo, Michael R. Betts, Carolyn Spencer, Barry J. Bryne, James M. Wilson, Terence R. Flotte
Christian Mueller
Alpha-1 antitrypsin (AAT) deficiency is well-suited as a target for human gene transfer. We performed a phase 1, open-label, dose-escalation clinical trial of a recombinant adeno-associated virus (rAAV) vector expressing normal (M) AAT packaged into serotype 1 AAV capsids delivered by i.m. injection. Nine AAT-deficient subjects were enrolled sequentially in cohorts of 3 each at doses of 6.9 x 10(12), 2.2 x 10(13), and 6.0 x 10(13) vector genome particles per patient. Four subjects receiving AAT protein augmentation discontinued therapy 28 or 56 days before vector administration. Vector administration was well tolerated, with only mild local reactions and 1 unrelated …
Sustained Mirna-Mediated Knockdown Of Mutant Aat With Simultaneous Augmentation Of Wild-Type Aat Has Minimal Effect On Global Liver Mirna Profiles, Christian Mueller, Qiushi Tang, Alisha Gruntman, Keith S. Blomenkamp, Jeffrey H. Teckman, Lina Song, Phillip D. Zamore, Terence R. Flotte
Sustained Mirna-Mediated Knockdown Of Mutant Aat With Simultaneous Augmentation Of Wild-Type Aat Has Minimal Effect On Global Liver Mirna Profiles, Christian Mueller, Qiushi Tang, Alisha Gruntman, Keith S. Blomenkamp, Jeffrey H. Teckman, Lina Song, Phillip D. Zamore, Terence R. Flotte
Christian Mueller
Alpha-1 antitrypsin (AAT) deficiency can exhibit two pathologic states: a lung disease that is primarily due to the loss of AAT's antiprotease function, and a liver disease resulting from a toxic gain-of-function of the PiZ-AAT (Z-AAT) mutant protein. We have developed several recombinant adeno-associated virus (rAAV) vectors that incorporate microRNA (miRNA) sequences targeting the AAT gene while also driving the expression of miRNA-resistant wild-type AAT-PiM (M-AAT) gene, thus achieving concomitant Z-AAT knockdown in the liver and increased expression of M-AAT. Transgenic mice expressing the human PiZ allele treated with dual-function rAAV9 vectors showed that serum PiZ was stably and persistently …