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- W3176288682 abstract "Genetic defects in the adenosine deaminase (ADA) gene are among the mostcommon causes for severe combined immunodeficiency (SCID). ADA-SCIDpatients suffer from lymphopenia, absent cellular and humoral immunity,recurrent infections and autoimmune manifestations in milder forms. Currentlyavailable therapeutic options for this otherwise fatal disorder include bonemarrow transplantation (BMT), enzyme replacement therapy with bovine ADA(PEG-ADA) or hematopoietic stem cell gene therapy (GT). The overall aims ofmy this thesis were to evaluate the preclinical safety of HSC gene therapy andthe basis involved in autoimmune manifestations observed in ADA deficiency.For the first part of the project I assessed the feasibility to perform two preclinicalstudies recommended by Regulatory Authorities:toxicology/tumorigenicity and biodistribution studies. Both studies wereperformed using the NSG immunodeficient mouse model transplanted withmurine or human hematopoietic stem/progenitor cells transduced with aRetroviral vector with an amphotrophic envelope encoding for ADA. For thetoxicology/tumorigenicity study we tested different transduction protocols both invitro and in vivo showing a low transduction efficiency in ADA-/- mouse lineagenegative cells. These results led us to conclude that this model is not suitablefor in vivo toxicology/tumorigenicity studies. On the other hand, transductionefficiency in human hematopoietic stem/progenitor cells was higher comparedto murine cells. Biodistribution study with human CD34+ cells derived from cordblood showed a good engraftment of human cells in NSG hosts with transducedcells in PB and lymphoid organs, in line with the frequency found in treated patients.The second part of my PhD project aimed at investigating Treg function and Bcell development in ADA-deficient mice. Autoimmune manifestations includingtype I diabetes, hypothyroidism, autoimmune thrombocytopenia, and haemolyticanaemia are frequently observed in the ADA-SCID patients treated with PEGADA,BMT and GT. We investigated the mechanisms which might be involvedin these alterations. We found that PEG_ADA treated mice represent a model tostudy autoimmunity as they developed multiple autoantibodies andhypothyroidism in contrast to mice treated with bone marrow transplantation orgene therapy. Moreover, Tregs isolated from PEG-ADA– treated mice lackedsuppressive activity, suggesting that this treatment interferes with Tregfunctionality.mice showed a mild alteration in the bone marrow and splenic B cell subsets.We also explored whether an increased egress of immature and recirculant Bcells from the bone marrow through the synovial vessels due to the activation ofendocannabinoid pathway might contribute to autoimmune manifestations inthis disease. B-cell escaping central tolerance mechanisms together with nonfunctionalTreg cells in the periphery might further accelerate the onset ofautoimmunity.In summary results of this work have contributed to improved our knowledge onADA-SCID and facilitate the progress of clinical development of gene therapy for ADA-SCID." @default.
- W3176288682 created "2021-07-05" @default.
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- W3176288682 date "2012-01-01" @default.
- W3176288682 modified "2023-09-23" @default.
- W3176288682 title "Preclinical gene therapy studies, altered lymphocyte development and function in ADA-SCID" @default.
- W3176288682 hasPublicationYear "2012" @default.
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