IU Indianapolis ScholarWorks :: Browsing by Subject "Genetic therapy"

Browsing by Subject "Genetic therapy"

Now showing 1 - 10 of 16

ASGCT 2021: Time to celebrate and expand
(Elsevier, 2021) Herzog, Roland W.; Frederickson, Robert; Pediatrics, School of Medicine
Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency
(Massachusetts Medical Society, 2021-05-27) Kohn, Donald B.; Booth, Claire; Shaw, Kit L.; Xu-Bayford, Jinhua; Garabedian, Elizabeth; Trevisan, Valentina; Carbonaro-Sarracino, Denise A.; Soni, Kajal; Terrazas, Dayna; Snell, Katie; Ikeda, Alan; Leon-Rico, Diego; Moore, Theodore B.; Buckland, Karen F.; Shah, Ami J.; Gilmour, Kimberly C.; De Oliveira, Satiro; Rivat, Christine; Crooks, Gay M.; Izotova, Natalia; Tse, John; Adams, Stuart; Shupien, Sally; Ricketts, Hilory; Davila, Alejandra; Uzowuru, Chilenwa; Icreverzi, Amalia; Barman, Provaboti; Fernandez, Beatriz Campo; Hollis, Roger P.; Coronel, Maritess; Yu, Allen; Chun, Krista M.; Casas, Christian E.; Zhang, Ruixue; Arduini, Serena; Lynn, Frances; Kudari, Mahesh; Spezzi, Andrea; Zahn, Marco; Heimke, Rene; Labik, Ivan; Parrott, Roberta; Buckley, Rebecca H.; Reeves, Lilith; Cornetta, Kenneth; Sokolic, Robert; Hershfield, Michael; Schmidt, Manfred; Candotti, Fabio; Malech, Harry L.; Thrasher, Adrian J.; Gaspar, H. Bobby; Medicine, School of Medicine
Background: Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency. Methods: We treated 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) with an investigational gene therapy composed of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a self-inactivating lentiviral vector encoding human ADA. Data from the two U.S. studies (in which fresh and cryopreserved formulations were used) at 24 months of follow-up were analyzed alongside data from the U.K. study (in which a fresh formulation was used) at 36 months of follow-up. Results: Overall survival was 100% in all studies up to 24 and 36 months. Event-free survival (in the absence of reinitiation of enzyme-replacement therapy or rescue allogeneic hematopoietic stem-cell transplantation) was 97% (U.S. studies) and 100% (U.K. study) at 12 months; 97% and 95%, respectively, at 24 months; and 95% (U.K. study) at 36 months. Engraftment of genetically modified HSPCs persisted in 29 of 30 patients in the U.S. studies and in 19 of 20 patients in the U.K. study. Patients had sustained metabolic detoxification and normalization of ADA activity levels. Immune reconstitution was robust, with 90% of the patients in the U.S. studies and 100% of those in the U.K. study discontinuing immunoglobulin-replacement therapy by 24 months and 36 months, respectively. No evidence of monoclonal expansion, leukoproliferative complications, or emergence of replication-competent lentivirus was noted, and no events of autoimmunity or graft-versus-host disease occurred. Most adverse events were of low grade. Conclusions: Treatment of ADA-SCID with ex vivo lentiviral HSPC gene therapy resulted in high overall and event-free survival with sustained ADA expression, metabolic correction, and functional immune reconstitution.
Challenges of cost-effectiveness analyses of novel therapeutics for Inherited Retinal Diseases
(Elsevier, 2022) Jayasundera, K. Thiran; Abuzaitoun, Rebhi O.; Lacy, Gabrielle D.; Abalem, Maria Fernanda; Saltzman, Gregory M.; Ciulla, Thomas A.; Johnson, Mark W.; Ophthalmology, School of Medicine
Purpose: To investigate the challenges and potential improvement strategies of cost-effectiveness analyses performed for therapeutics targeting inherited retinal diseases (IRDs). Design: Perspective. Methods: A literature review was conducted with discussion of current limitations and improvement recommendations. Results: Cost-effectiveness analysis (CEA) performed for IRD therapeutics has multiple limitations. First, the available methods used to measure health-related quality of life and health utilities can be inaccurate when used in IRDs. Second, the financial burden to patients and society from vision impairment associated with IRDs has been inadequately studied and includes a variety of expenditures ranging from direct costs of IRD specialty health care to indirect expenses associated with daily living activities. Third, our collective understanding is limited in the areas of IRD natural history and health benefits gained from new IRD treatments (eg, gene therapies). In addition, the therapeutic effect from a patient perspective and its duration of action are not fully understood. Due to the scarcity of data, CEA for newly approved therapies has relied on assumptions and creations of predictive models for both costs and health benefits for these new therapeutics in order to calculate the incremental cost-effectiveness ratio. Conclusions: CEA studies performed for IRD therapeutics have been limited by the established health utilities in ophthalmology and the lack of disease-specific information. The assumptions and extrapolations in these studies create substantial uncertainty in incremental cost-effectiveness ratio results. An improved framework is required for CEA of IRD therapeutics in order to determine the cost-effectiveness of each therapy brought from clinical trials to clinical practice.
Curing Hemophilia: Repeated Treatments versus a One-Off Fix
(Elsevier, 2020-05-06) Li, Ning; Kaczmarek, Radoslaw; Pediatrics, School of Medicine
Did Dendritic Cell Activation, Induced by Adenovirus-Antibody Complexes, Play a Role in the Death of Jesse Gelsinger?
(Elsevier, 2020-03-04) Baker, Andrew H.; Herzog, Roland W.; Pediatrics, School of Medicine
First conditional marketing authorization approval in the European Union for hemophilia "A" gene therapy
(Elsevier, 2022) VandenDriessche, Thierry; Pipe, Steven W.; Pierce, Glenn F.; Kaczmarek, Radoslaw; Pediatrics, School of Medicine
First hemophilia B gene therapy approved: More than two decades in the making
(Elsevier, 2023) Herzog, Roland W.; VandenDriessche, Thierry; Ozelo, Margareth C.; Pediatrics, School of Medicine
Implementation of a gene therapy education initiative by the ASGCT and Muhimbili University of Health and Allied Sciences
(Elsevier, 2023) Cornetta, Kenneth; Kay, Samantha; Urio, Florence; Minja, Irene Kida; Mbugi, Erasto; Mgaya, Josephine; Mselle, Teddy; Nkya, Siana; Alimohamed, Mohamed Zahir; Ndaki, Kinuma; Bonamino, Martín; Koya, Richard C.; Shah, Lesha D.; Mahlangu, Johnny; Drago, Daniela; Rangarajan, Savita; Jayandharan, Giridhara Rao; Medical and Molecular Genetics, School of Medicine
There has been rapid growth in gene therapy development with an expanding list of approved clinical products. Several therapies are particularly relevant to patients in low- and middle-income countries. Moreover, investing in research and manufacturing presents an opportunity for economic development. To increase awareness of gene therapy, the American Society of Gene and Cell Therapy partnered with the Muhimbili University of Health and Allied Sciences, Tanzania, to create a certificate-bearing course. The goal was to provide faculty teaching in graduate and medical schools with the tools needed to add gene therapy to the university curriculum. The first virtual course was held in October of 2022, and 45 individuals from 9 countries in Africa completed the training. The content was new to approximately two-thirds of participants, with the remaining third indicating that the course increased their knowledge base. The program was well received and will be adapted for other under-resourced regions.
Influence of N-glycosylation in the A and C domains on the immunogenicity of factor VIII
(American Society of Hematology, 2022) Vander Kooi, Amber; Wang, Shuaishuai; Fan, Meng-Ni; Chen, Alex; Zhang, Junping; Chen, Chun-Yu; Cai, Xiaohe; Konkle, Barbara A.; Xiao, Weidong; Li, Lei; Miao, Carol H.; Pediatrics, School of Medicine
The most significant complication in hemophilia A treatment is the formation of inhibitors against factor VIII (FVIII) protein. Glycans and glycan-binding proteins are central to a properly functioning immune system. This study focuses on whether glycosylation of FVIII plays an important role in induction and regulation of anti-FVIII immune responses. We investigated the potential roles of 4 N-glycosylation sites, including N41 and N239 in the A1 domain, N1810 in the A3 domain, and N2118 in the C1 domain of FVIII, in moderating its immunogenicity. Glycomics analysis of plasma-derived FVIII revealed that sites N41, N239, and N1810 contain mostly sialylated complex glycoforms, while high mannose glycans dominate at site N2118. A missense variant that substitutes asparagine (N) to glutamine (Q) was introduced to eliminate glycosylation on each of these sites. Following gene transfer of plasmids encoding B domain deleted FVIII (BDD-FVIII) and each of these 4 FVIII variants, it was found that specific activity of FVIII in plasma remained similar among all treatment groups. Slightly increased or comparable immune responses in N41Q, N239Q, and N1810Q FVIII variant plasmid-treated mice and significantly decreased immune responses in N2118Q FVIII plasmid-treated mice were observed when compared with BDD-FVIII plasmid-treated mice. The reduction of inhibitor response by N2118Q FVIII variant was also demonstrated in AAV-mediated gene transfer experiments. Furthermore, a specific glycopeptide epitope surrounding the N2118 glycosylation site was identified and characterized to activate T cells in an FVIII-specific proliferation assay. These results indicate that N-glycosylation of FVIII can have significant impact on its immunogenicity.
Liver gene therapy and hepatocellular carcinoma: A complex web
(Elsevier, 2021) de Jong, Ype P.; Herzog, Roland W.; Pediatrics, School of Medicine

Browsing by Subject "Genetic therapy"

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