A5001371229- Virus-based gene therapy research
- CAR-T cell therapy research
- CRISPR and Genetic Engineering
- RNA Interference and Gene Delivery
- Hemoglobinopathies and Related Disorders
- Pluripotent Stem Cells Research
- Cellular Mechanics and Interactions
- Cell Adhesion Molecules Research
- Immunodeficiency and Autoimmune Disorders
- Viral Infectious Diseases and Gene Expression in Insects
- Erythrocyte Function and Pathophysiology
- Immune Cell Function and Interaction
- Cytomegalovirus and herpesvirus research
- Platelet Disorders and Treatments
- Hematopoietic Stem Cell Transplantation
- Parvovirus B19 Infection Studies
- Prenatal Screening and Diagnostics
- Phagocytosis and Immune Regulation
- T-cell and B-cell Immunology
- Mesenchymal stem cell research
- Immunotherapy and Immune Responses
- Viral Infections and Immunology Research
- Adenosine and Purinergic Signaling
- Wound Healing and Treatments
- Myeloproliferative Neoplasms: Diagnosis and Treatment
Istituti di Ricovero e Cura a Carattere Scientifico
2015-2024
The San Raffaele Telethon Institute for Gene Therapy
2013-2024
Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele
2015-2023
Humanitas University
2015
Institute of Genetic and Biomedical Research
2012-2015
IRCCS Ospedale San Raffaele
2007-2009
Vita-Salute San Raffaele University
2006-2009
San Raffaele University of Rome
2008
Wiskott-Aldrich syndrome (WAS) is an inherited immunodeficiency caused by mutations in the gene encoding WASP, a protein regulating cytoskeleton. Hematopoietic stem/progenitor cell (HSPC) transplants can be curative, but, when matched donors are unavailable, infusion of autologous HSPCs modified ex vivo therapy alternative approach. We used lentiviral vector functional WASP to genetically correct from three WAS patients and reinfused cells after reduced-intensity conditioning regimen. All...
We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to lack adenosine deaminase (ADA), a fatal disorder purine metabolism and immunodeficiency.
Hematopoietic stem/progenitor cells (HSPCs) are capable of supporting the lifelong production blood exerting a wide spectrum functions. Lentiviral vector HSPC gene therapy generates human hematopoietic system stably marked at clonal level by integration sites (ISs). Using IS analysis, we longitudinally tracked >89,000 clones from 15 distinct bone marrow and peripheral lineages purified up to 4 years after transplant in four Wiskott-Aldrich syndrome patients treated with therapy. We measured...
Wiskott-Aldrich syndrome is a rare, life-threatening, X-linked primary immunodeficiency characterised by microthrombocytopenia, infections, eczema, autoimmunity, and malignant disease. Lentiviral vector-mediated haemopoietic stem/progenitor cell (HSPC) gene therapy potentially curative treatment that represents an alternative to allogeneic HSPC transplantation. Here, we report safety efficacy data from interim analysis of patients with severe who received lentiviral vector-derived therapy.We...
Gene transfer into HSCs is an effective treatment for SCID, although potentially limited by the risk of insertional mutagenesis. We performed a genome-wide analysis retroviral vector integrations in genetically corrected and their multilineage progeny before up to 47 months after transplantation 5 patients with adenosine deaminase–deficient SCID. Gene-dense regions, promoters, transcriptionally active genes were preferred sites (RISs) both preinfusion transduced CD34+ cells vivo gene...
A large proportion of Wiskott-Aldrich syndrome (WAS) patients develop autoimmunity and allergy. CD4+CD25+FOXP3+ natural regulatory T (nTreg) cells play a key role in peripheral tolerance to prevent immune responses self-antigens allergens. Therefore, we investigated the effect WAS protein (WASP) deficiency on distribution suppressor function nTreg cells. In WAS−/− mice, steady-state phenotype thymus spleen were normal. However, engrafted poorly immunized indicating perturbed homeostasis....
Wiskott-Aldrich Syndrome protein (WASp) regulates the cytoskeleton in hematopoietic cells and mutations its gene cause (WAS), a primary immunodeficiency with microthrombocytopenia, eczema higher susceptibility to develop tumors. Autoimmune manifestations, frequently observed WAS patients, are associated an increased risk of mortality still represent unsolved aspect disease. B play crucial role both immune competence self-tolerance defects their development function result and/or...
Gene therapy with ex vivo-transduced hematopoietic stem/progenitor cells may represent a valid therapeutic option for monogenic immunohematological disorders such as Wiskott-Aldrich syndrome (WAS), primary immunodeficiency associated thrombocytopenia. We evaluated the preclinical safety and efficacy of human CD34+ transduced lentiviral vectors (LV) encoding WAS protein (WASp). first set up validated transduction protocol derived from bone marrow (BM) or mobilized peripheral blood (MPB) using...
Wiskott-Aldrich syndrome (WAS) protein (WASP) plays a key role in TCR-mediated activation and immunological synapse formation. However, the effects of WASP deficiency on effector functions human CD4+ CD8+ T cells remain to be determined. In this study, we report that TCR/CD28-driven proliferation secretion IL-2, IFN-gamma, TNF-alpha are strongly reduced from WAS patients, compared with healthy donor cells. Furthermore, secrete low levels IL-2 fail produce IFN-gamma TNF-alpha, while...
Wiskott-Aldrich Syndrome (WAS) is a life-threatening X-linked disease characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancies. Gene therapy could represent therapeutic option for patients lacking suitable bone marrow (BM) donor. In this study, we analyzed the long-term outcome of WAS gene mediated clinically compatible lentiviral vector (LV) in large cohort was(null) mice. We demonstrated stable full donor engraftment protein (WASP) expression various...
Regulated transgene expression may improve the safety and efficacy of hematopoietic stem cell (HSC) gene therapy. Clinical trials for X-linked chronic granulomatous disease (X-CGD) employing gammaretroviral vectors were limited by insertional oncogenesis or lack persistent engraftment. Our novel strategy, based on regulated lentiviral (LV), targets gp91phox to differentiated myeloid compartment while sparing HSC, reduce risk genotoxicity potential perturbation reactive oxygen species levels....
BACKGROUND. The human bone marrow (BM) niche contains a population of mesenchymal stromal cells (MSCs) that provide physical support and regulate hematopoietic stem cell (HSC) homeostasis. β-Thalassemia (BT) is hereditary disorder characterized by altered hemoglobin beta-chain synthesis amenable to allogeneic HSC transplantation gene therapy. Iron overload (IO) common complication in BT patients affecting several organs. However, data on the BM compartment are scarce.
β-Thalassemia (BT) is one of the most common genetic diseases worldwide and caused by mutations affecting β-globin production. The only curative treatment allogenic hematopoietic stem/progenitor cells (HSPCs) transplantation, an approach limited compatible donor availability immunological complications. Therefore, transplantation autologous, genetically-modified HSPCs attractive therapeutic option. However, current gene therapy strategies based on use lentiviral vectors are not equally...
Wiskott-Aldrich syndrome (WAS) is a life-threatening X-linked primary immunodeficiency characterized by infections, hemorrhages, autoimmune disorders, and lymphomas. Transplantation of genetically corrected autologous hematopoietic stem cells (HSCs) could represent an alternative treatment to allogeneic HSC transplantation, the latter being often associated with severe complications. We used WAS –/– mice test efficacy gene therapy approach based on nonlethal irradiation followed...
Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by microthrombocytopenia, eczema, and high susceptibility to developing tumors autoimmunity. Recent evidence suggests that B cells may be key players in the pathogenesis of autoimmunity WAS. Here, we assessed whether WAS protein deficiency (WASp deficiency) affects establishment cell tolerance testing reactivity recombinant antibodies isolated from single 4 patients before after gene therapy (GT). We found pre-GT...
Wiskott-Aldrich syndrome (WAS) is a severe X-linked immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infections, and susceptibility to autoimmunity lymphomas. Hematopoietic stem cell transplantation the treatment of choice; however, administration WAS gene-corrected autologous hematopoietic cells has been demonstrated as feasible alternative therapeutic approach.Because B-cell homeostasis perturbed in patients with restoration immune competence one main goals, we...
Sickle cell disease (SCD) is due to a mutation in the β-globin gene causing production of toxic sickle hemoglobin (HbS; α2βS2). Transplantation autologous hematopoietic stem and progenitor cells (HSPCs) transduced with lentiviral vectors (LVs) expressing an anti-sickling (βAS) promising treatment; however, it only partially effective, patients still present elevated HbS levels. Here, we developed bifunctional LV βAS3-globin artificial microRNA (amiRNA) specifically downregulating βS-globin...