Search

Your search keyword '"Nadia A. Kadry"' showing total 6 results
Start Over Author "Nadia A. Kadry"
6 results on '"Nadia A. Kadry"'

1. T cell dynamics and response of the microbiota after gene therapy to treat X-linked severe combined immunodeficiency

Author

Erik L. Clarke, A. Jesse Connell, Emmanuelle Six, Nadia A. Kadry, Arwa A. Abbas, Young Hwang, John K. Everett, Casey E. Hofstaedter, Rebecca Marsh, Myriam Armant, Judith Kelsen, Luigi D. Notarangelo, Ronald G. Collman, Salima Hacein-Bey-Abina, Donald B. Kohn, Marina Cavazzana, Alain Fischer, David A. Williams, Sung-Yun Pai, and Frederic D. Bushman

Subjects
Medicine, Genetics, QH426-470
Abstract

Abstract Background Mutation of the IL2RG gene results in a form of severe combined immune deficiency (SCID-X1), which has been treated successfully with hematopoietic stem cell gene therapy. SCID-X1 gene therapy results in reconstitution of the previously lacking T cell compartment, allowing analysis of the roles of T cell immunity in humans by comparing before and after gene correction. Methods Here we interrogate T cell reconstitution using four forms of high throughput analysis. (1) Estimation of the numbers of transduced progenitor cells by monitoring unique positions of integration of the therapeutic gene transfer vector. (2) Estimation of T cell population structure by sequencing of the recombined T cell receptor (TCR) beta locus. (3) Metagenomic analysis of microbial populations in oropharyngeal, nasopharyngeal, and gut samples. (4) Metagenomic analysis of viral populations in gut samples. Results Comparison of progenitor and mature T cell populations allowed estimation of a minimum number of cell divisions needed to generate the observed populations. Analysis of microbial populations showed the effects of immune reconstitution, including normalization of gut microbiota and clearance of viral infections. Metagenomic analysis revealed enrichment of genes for antibiotic resistance in gene-corrected subjects relative to healthy controls, likely a result of higher healthcare exposure. Conclusions This multi-omic approach enables the characterization of multiple effects of SCID-X1 gene therapy, including T cell repertoire reconstitution, estimation of numbers of cell divisions between progenitors and daughter T cells, normalization of the microbiome, clearance of microbial pathogens, and modulations in antibiotic resistance gene levels. Together, these results quantify several aspects of the long-term efficacy of gene therapy for SCID-X1. This study includes data from ClinicalTrials.gov numbers NCT01410019, NCT01175239, and NCT01129544.

Published
2018
Full Text
View/download PDF

3. Contributors

Author

Mark J. Abzug, Elisabeth E. Adderson, Aastha Agarwal, Allison L. Agwu, Lindsey Albenberg, Jonathan Albert, Kevin Alby, Grace M. Aldrovandi, Upton D. Allen, Gerardo Alvarez-Hernndez, Krow Ampofo, Evan J. Anderson, Grace D. Appiah, Monica I. Ardura, Stephen S. Arnon, Naomi E. Aronson, Ann M. Arvin, Shai Ashkenazi, Liat Ashkenazi-Hoffnung, Edwin J. Asturias, Kestutis Aukstuolis, Vahe Badalyan, Carol J. Baker, Karthik Balakrishnan, Elizabeth D. Barnett, Kirsten Bechtel, William E. Benitz, Rachel Berkovich, David M. Berman, Stephanie R. Bialek, Else M. Bijker, Matthew J. Bizzarro, Karen C. Bloch, Joseph A. Bocchini, Thomas G. Boyce, John S. Bradley, Denise F. Bratcher, Paula K. Braverman, Itzhak Brook, Kevin Edward Brown, Kristina P. Bryant, Andres F. Camacho-Gonzalez, Connie F. Caete-Gibas, Joseph B. Cantey, Paul Cantey, Cristina V. Cardemil, Mary T. Caserta, Luis A. Castagnini, Jessica R. Cataldi, Ellen Gould Chadwick, Rebecca J. Chancey, Cara C. Cherry, Silvia S. Chiang, Mary Choi, John C. Christenson, Susan E. Coffin, Amanda Cohn, Despina G. Contopoulos-Ioannidis, James H. Conway, Margaret M. Cortese, C. Buddy Creech, Jonathan D. Crews, Donna Curtis, Nigel Curtis, Lara A. Danziger-Isakov, Toni Darville, Gregory A. Dasch, Irini Daskalaki, H. Dele Davies, Fatimah S. Dawood, J. Christopher Day, M. Teresa de la Morena, Gregory P. DeMuri, Dickson D. Despommier, Daniel S. Dodson, Stephen J. Dolgner, Clinton Dunn, Jonathan Dyal, Kathryn M. Edwards, Morven S. Edwards, Dawn Z. Eichenfield, Lawrence F. Eichenfield, Dirk M. Elston, Beth Emerson, Leslie A. Enane, Moshe Ephros, Guliz Erdem, Marina E. Eremeeva, Douglas H. Esposito, Monica M. Farley, Anat R. Feingold, Kristina N. Feja, Adam Finn, Marc Fischer, Brian T. Fisher, Randall G. Fisher, Patricia Michele Flynn, Monique A. Foster, LeAnne M. Fox, Michael M. Frank, Douglas R. Fredrick, Robert W. Frenck, James Gaensbauer, Hayley A. Gans, Gregory M. Gauthier, Patrick Gavigan, Jeffrey S. Gerber, Yael Gernez, Francis Gigliotti, Mark A. Gilger, Carol A. Glaser, Jane M. Gould, James Graziano, Amanda M. Green, Michael Green, Daniel Griffin, Patricia M. Griffin, David C. Griffith, Piyush Gupta, Bruce J. Gutelius, Julie R. Gutman, Aron J. Hall, Rana F. Hamdy, Jin-Young Han, Lori K. Handy, Benjamin Hanisch, Marvin B. Harper, Aaron M. Harris, Christopher J. Harrison, David B. Haslam, Julia C. Haston, Sarah.J. Hawkes, Taylor Heald-Sargent, J. Owen Hendley, Adam L. Hersh, Joseph A. Hilinski, Susan L. Hills, David K. Hong, Peter J. Hotez, Katherine K. Hsu, Felicia Scaggs Huang, David A. Hunstad, W. Garrett Hunt, Loris Y. Hwang, Christelle M. Ilboudo, Preeti Jaggi, Sophonie Jean, Ravi Jhaveri, Kateina Jirk-Pomajbkov, Nadia A. Kadry, Mary L. Kamb, Ronak K. Kapadia, Ben Z. Katz, Sophie E. Katz, Ishminder Kaur, Gilbert J. Kersh, Muhammad Ali Khan, Ananta Khurana, David W. Kimberlin, Bruce Klein, Miwako Kobayashi, Larry K. Kociolek, Andrew Y. Koh, Karen L. Kotloff, Andrew T. Kroger, Matthew P. Kronman, Leah Lalor, Christine T. Lauren, Amy Leber, Eyal Leshem, David B. Lewis, Robyn A. Livingston, Eloisa Llata, Kevin Lloyd, Katrina Loh, Sarah S. Long, Benjamin A. Lopman, Yalda C. Lucero, Debra J. Lugo, Jorge Lujn-Zilbermann, Yvonne A. Maldonado, John J. Manaloor, Kalpana Manthiram, Stacey W. Martin, Roshni Mathew, Tony Mazzulli, Elizabeth J. McFarland, Kathleen A. McGann, Lucy A. McNamara, Debrah Meislich, H. Cody Meissner, Asuncion Mejias, Jussi Mertsola, Kevin Messacar, Mohammad Nael Mhaissen, Marian G. Michaels, Melissa B. Miller, Hilary Miller-Handley, Eric Mintz, Parvathi Mohan, Susan P. Montgomery, Jose G. Montoya, Anne C. Moorman, Pedro L. Moro, Anna-Barbara Moscicki, William J. Muller, Angela L. Myers, Simon Nadel, Jennifer Lynn Nayak, Michael Noel Neely, Karen P. Neil, Christina A. Nelson, Noele P. Nelson, Megin Nichols, William Nicholson, Amy Jo Nopper, Laura E. Norton, Theresa J. Ochoa, Liset Olarte, Timothy R. Onarecker, Walter A. Orenstein, Miguel ORyan, William R. Otto, Christopher P. Ouellette, Christopher D. Paddock, Debra L. Palazzi, Suresh Kumar Panuganti, Diane E. Pappas, Michal Paret, Daniel M. Pastula, Thomas F. Patterson, Brett W. Petersen, Mikael Petrosyan, Larry K. Pickering, Talia Pindyck, Swetha Pinninti, Laure F. Pittet, Paul J. Planet, Andrew J. Pollard, Klara M. Posfay-Barbe, Casper S. Poulsen, Susan M. Poutanen, Ann M. Powers, Nina Salinger Prasanphanich, Bobbi S. Pritt, Charles G. Prober, Neha Puar, Laura A.S. Quilter, Octavio Ramilo, Suchitra Rao, Adam J. Ratner, Sarah A. Rawstron, Jennifer S. Read, Ryan F. Relich, Megan E. Reller, Candice L. Robinson, Jos R. Romero, David A. Rosen, Shannon A. Ross, G. Ingrid J.G. Rours, Peter C. Rowe, Anne H. Rowley, Lorry G. Rubin, Edward T. Ryan, Alexandra Sacharok, Thomas J. Sandora, Sarah G.H. Sapp, Kabir Sardana, Jason B. Sauberan, Joshua K. Schaffzin, Sarah Schillie, Jennifer E. Schuster, Kevin L. Schwartz, Bethany K. Sederdahl, Jose Serpa-Alvarez, Kara N. Shah, Samir S. Shah, Nader Shaikh, Andi L. Shane, Eugene D. Shapiro, Jana Shaw, Avinash K. Shetty, Timothy R. Shope, Linda M. Dairiki Shortliffe, Stanford T. Shulman, Gail F. Shust, George Kelly Siberry, Jane D. Siegel, Robert David Siegel, Kari A. Simonsen, Upinder Singh, Christiana Smith, Lauren L. Smith, Eunkyung Song, Emily Souder, Paul Spearman, Joseph W. St. Geme, Mary Allen Staat, J. Erin Staples, Jeffrey R. Starke, Victoria A. Statler, William J. Steinbach, Christen Rune Stensvold, Erin K. Stokes, Bradley P. Stoner, Gregory A. Storch, Anne Straily, Kathleen E. Sullivan, Douglas S. Swanson, Robert R. Tanz, Gillian Taormina, Jacqueline E. Tate, Jeanette Taveras, Marc Tebruegge, Eyasu H. Teshale, George R. Thompson, Robert Thompson-Stone, Isaac Thomsen, Richard B. Thomson, Emily A. Thorell, Vivian Tien, Nicole H. Tobin, Philip Toltzis, James Treat, Stephanie B. Troy, Russell B. Van Dvke, Louise Elaine Vaz, Vini Vijayan, Jennifer Vodzak, Thor A. Wagner, Ellen R. Wald, Rebecca Wallihan, Huanyu Wang, Zoon Wangu, Matthew Washam, Valerie Waters, Joshua R. Watson, Jill E. Weatherhead, Geoffrey A. Weinberg, Mark K. Weng, Nathan P. Wiederhold, Harold C. Wiesenfeld, Cydni Williams, John V. Williams, Rodney E. Willoughby, Robert R. Wittler, James B. Wood, Charles Reece Woods, Kimberly A. Workowski, Terry W. Wright, Hsi-Yang Wu, Huan Xu, Pablo Yagupsky, Jumi Yi, Jonathan Yoder, Edward J. Young, Andrea L. Zaenglein, Petra Zimmermann, and Wenjing Zong

Published
2023
Full Text
View/download PDF

4. 2235. Discordance of Clinical and Microbiological Endpoints in Clinical Trials for Complicated Urinary Tract Infection (cUTI)

Author

Nadia A Kadry, Mukil Natarajan, Edward Bein, Peter Kim, and John Farley

Subjects
Infectious Diseases, Oncology
Abstract

Background Complicated urinary tract infections (cUTI) are a clinical syndrome characterized by pyuria and a documented microbial pathogen on urine or blood culture, accompanied by local and systemic signs and symptoms, in the presence of urinary tract abnormalities or acute pyelonephritis. Current FDA guidance recommends that the primary endpoint for cUTI clinical trials be a composite of the clinical and microbiological responses, assessed at a fixed time after therapy. In recent trials, it has been noted that while some patients have clinical resolution of symptoms, they are considered failures due to positive urine cultures. These discordant outcomes have raised questions about the utility of the microbiological endpoint. Methods We analyzed patient data from 13 phase 3 clinical trials submitted to the FDA. We focused on the microbiological modified intent-to-treat (m-MITT) population, including patients who have at least 1 bacterial pathogen known to cause cUTI and received at least one dose of study drug (N=4842). Outcomes were determined at the Test of Cure (TOC) visit 7-10 days after therapy, and the Late Follow Up (LFU) visit 3-4 weeks after therapy. Clinical and microbiological success were defined as the resolution of cUTI symptoms present at entry, with no new symptoms (clinical cure), and reduction of the pathogen at entry to ≤ 103 CFU/mL on urine culture (microbiological eradication). Results Among all included patients, 70.7% were overall successes at the TOC, exhibiting clinical and microbiological success. 18.0% were discordant failures (clinical cure/microbiological persistence), and 6.7% were concordant failures (clinical failure/microbiological persistence). In a multivariate logistic regression model, discordance was associated with obesity, lithiasis, use of analgesics, and receipt of carbapenem antibiotics. Discordant patients were at an increased risk for clinical failure at the LFU visit, and the risk of late clinical failure increased with longer time between the TOC and LFU visits. Conclusion Microbiological persistence at the TOC visit despite resolution of symptoms was associated with an increased risk of late clinical failure. Microbiological outcomes appear to be an important component in the composite endpoint. Disclosures All Authors: No reported disclosures.

Published
2022
Full Text
View/download PDF

5. Immunization with HMW1 and HMW2 adhesins protects against colonization by heterologous strains of nontypeable Haemophilus influenzae

Author

Hao Shen, Nadia A. Kadry, Eric A. Porsch, and Joseph W. St. Geme

Subjects
Haemophilus Infections, Heterologous, Biology, medicine.disease_cause, Bacterial Adhesion, Haemophilus influenzae, Microbiology, Pathogenesis, Agglutination Tests, Nasopharynx, medicine, otorhinolaryngologic diseases, Animals, Colonization, Adhesins, Bacterial, Mice, Inbred BALB C, Multidisciplinary, Interleukin-17, Biological Sciences, Antibodies, Bacterial, Bacterial adhesin, medicine.anatomical_structure, Immunization, biology.protein, Female, Antibody, Respiratory tract
Abstract

Nontypeable Haemophilus influenzae (NTHi) is a common cause of localized respiratory tract disease and results in significant morbidity. The pathogenesis of NTHi disease begins with nasopharyngeal colonization, and therefore, the prevention of colonization represents a strategy to prevent disease. The NTHi HMW1 and HMW2 proteins are a family of conserved adhesins that are present in 75 to 80% of strains and have been demonstrated to play a critical role in colonization of the upper respiratory tract in rhesus macaques. In this study, we examined the vaccine potential of HMW1 and HMW2 using a mouse model of nasopharyngeal colonization. Immunization with HMW1 and HMW2 by either the subcutaneous or the intranasal route resulted in a strain-specific antibody response associated with agglutination of bacteria and restriction of bacterial adherence. Despite the specificity of the antibody response, immunization resulted in protection against colonization by both the parent NTHi strain and heterologous strains expressing distinct HMW1 and HMW2 proteins. Pretreatment with antibody against IL-17A eliminated protection against heterologous strains, indicating that heterologous protection is IL-17A dependent. This work demonstrates the vaccine potential of the HMW1 and HMW2 proteins and highlights the importance of IL-17A in protection against diverse NTHi strains.

Published
2021

6. T cell dynamics and response of the microbiota after gene therapy to treat X-linked severe combined immunodeficiency

Author

Nadia A. Kadry, A. Jesse Connell, Emmanuelle Six, Rebecca A. Marsh, Marina Cavazzana, Ronald G. Collman, Alain Fischer, Erik L. Clarke, Sung-Yun Pai, David A. Williams, Myriam Armant, Judith R. Kelsen, Arwa Abbas, Luigi D. Notarangelo, Frederic D. Bushman, Young Hwang, John K. Everett, Donald B. Kohn, Salima Hacein-Bey-Abina, Casey E. Hofstaedter, University of Pennsylvania School of Veterinary Medicine, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Cincinnati Children's Hospital Medical Center, Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), University of California, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), University of California (UC), and ORANGE, Colette

Subjects
0301 basic medicine, SELECTION, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Genetic enhancement, Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocytes, lcsh:Medicine, Regenerative Medicine, X-Linked Combined Immunodeficiency Diseases, Receptors, Child, Genetics (clinical), INTERLEUKIN-2, alpha-beta, SITES, Microbiota, Hematopoietic stem cell, Gene Therapy, ASSOCIATION, EXPANSION, 3. Good health, medicine.anatomical_structure, SCID PATIENTS, Antigen, Child, Preschool, Molecular Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Infection, Cell Division, Biotechnology, [SDV.IMM] Life Sciences [q-bio]/Immunology, lcsh:QH426-470, T cell, Clinical Sciences, VECTOR, Biology, 03 medical and health sciences, Immune system, Clinical Research, medicine, Genetics, Humans, X-linked severe combined immunodeficiency, Progenitor cell, Preschool, Molecular Biology, Gene, Inflammatory and immune system, Research, T-cell receptor, lcsh:R, DNA INTEGRATION, HIV, Genetic Therapy, medicine.disease, T-Cell, Stem Cell Research, Complementarity Determining Regions, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, lcsh:Genetics, 030104 developmental biology, TRANSPLANT, Immunology
Abstract

Background Mutation of the IL2RG gene results in a form of severe combined immune deficiency (SCID-X1), which has been treated successfully with hematopoietic stem cell gene therapy. SCID-X1 gene therapy results in reconstitution of the previously lacking T cell compartment, allowing analysis of the roles of T cell immunity in humans by comparing before and after gene correction. Methods Here we interrogate T cell reconstitution using four forms of high throughput analysis. (1) Estimation of the numbers of transduced progenitor cells by monitoring unique positions of integration of the therapeutic gene transfer vector. (2) Estimation of T cell population structure by sequencing of the recombined T cell receptor (TCR) beta locus. (3) Metagenomic analysis of microbial populations in oropharyngeal, nasopharyngeal, and gut samples. (4) Metagenomic analysis of viral populations in gut samples. Results Comparison of progenitor and mature T cell populations allowed estimation of a minimum number of cell divisions needed to generate the observed populations. Analysis of microbial populations showed the effects of immune reconstitution, including normalization of gut microbiota and clearance of viral infections. Metagenomic analysis revealed enrichment of genes for antibiotic resistance in gene-corrected subjects relative to healthy controls, likely a result of higher healthcare exposure. Conclusions This multi-omic approach enables the characterization of multiple effects of SCID-X1 gene therapy, including T cell repertoire reconstitution, estimation of numbers of cell divisions between progenitors and daughter T cells, normalization of the microbiome, clearance of microbial pathogens, and modulations in antibiotic resistance gene levels. Together, these results quantify several aspects of the long-term efficacy of gene therapy for SCID-X1. This study includes data from ClinicalTrials.gov numbers NCT01410019, NCT01175239, and NCT01129544. Electronic supplementary material The online version of this article (10.1186/s13073-018-0580-z) contains supplementary material, which is available to authorized users.

Published
2018
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results