13 results on '"Rivella, Stefano"'
Search Results
2. A combined approach for β-thalassemia based on gene therapy-mediated adult hemoglobin (HbA) production and fetal hemoglobin (HbF) induction
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Zuccato, Cristina, Breda, Laura, Salvatori, Francesca, Breveglieri, Giulia, Gardenghi, Sara, Bianchi, Nicoletta, Brognara, Eleonora, Lampronti, Ilaria, Borgatti, Monica, Rivella, Stefano, and Gambari, Roberto
- Published
- 2012
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3. Gene Therapy for Beta-Hemoglobinopathies: Milestones, New Therapies and Challenges.
- Author
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Ghiaccio, Valentina, Chappell, Maxwell, Rivella, Stefano, and Breda, Laura
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GENE therapy ,FETAL hemoglobin ,GENOME editing ,HEMATOPOIETIC stem cells ,BONE marrow transplantation ,GENETIC transformation - Abstract
Inherited monogenic disorders such as beta-hemoglobinopathies (BH) are fitting candidates for treatment via gene therapy by gene transfer or gene editing. The reported safety and efficacy of lentiviral vectors in preclinical studies have led to the development of several clinical trials for the addition of a functional beta-globin gene. Across trials, dozens of transfusion-dependent patients with sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT) have been treated via gene therapy and have achieved reduced transfusion requirements. While overall results are encouraging, the outcomes appear to be strongly influenced by the level of lentiviral integration in transduced cells after engraftment, as well as the underlying genotype resulting in thalassemia. In addition, the method of procurement of hematopoietic stem cells can affect their quality and thus the outcome of gene therapy both in SCD and TDT. This suggests that new studies aimed at maximizing the number of corrected cells with long-term self-renewal potential are crucial to ensure successful treatment for every patient. Recent advancements in gene transfer and bone marrow transplantation have improved the success of this approach, and the results obtained by using these strategies demonstrated significant improvement of gene transfer outcome in patients. The advent of new gene-editing technologies has suggested additional therapeutic options. These are primarily focused on correcting the defective beta-globin gene or editing the expression of genes or genomic segments that regulate fetal hemoglobin synthesis. In this review, we aim to establish the potential benefits of gene therapy for BH, to summarize the status of the ongoing trials, and to discuss the possible improvement or direction for future treatments. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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4. A preclinical approach for gene therapy of beta-thalassemia
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Breda, Laura, Kleinert, Dorothy A., Casu, Carla, Casula, Laura, Cartegni, Luca, Fibach, Eitan, Mancini, Irene, Giardina, Patricia J., Gambari, Roberto, and Rivella, Stefano
- Subjects
Genetic Vectors ,Lentivirus ,beta-Thalassemia ,lentiviral vectors ,Genetic Therapy ,beta-Globins ,hemoglobin ,β-globin ,erythroid progenitor cells ,gene therapy ,β-thalassemia ,Article ,NO ,Mice ,Mutation ,Animals ,Humans ,Cells, Cultured - Abstract
Lentiviral-mediated beta-globin gene transfer successfully treated beta-thalassemic mice. Based on this result, clinical trials were initiated. To date, however, no study has investigated the efficacy of gene therapy in relation to the nature of the different beta-globin mutations found in patients. Most mutations can be classified as beta(0) or beta(+), based on the amount of beta-globin protein produced. Therefore, we propose that a screening in vitro is necessary to verify the efficacy of gene transfer prior to treatment of individual patients. We used a two-phase liquid culture system to expand and differentiate erythroid progenitor cells (ErPCs) transduced with lentiviral vectors. We propose the use of this system to test the efficiency of lentiviral vectors carrying the human beta-globin gene, to correct the phenotype of ErPCs from patients preparing for gene therapy. This new approach might have profound implications for designing gene therapy and for understanding the genotype/phenotype variability observed in Cooley's anemia patients.
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- 2010
5. A validated cellular biobank for β-thalassemia.
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Cosenza, Lucia Carmela, Breda, Laura, Breveglieri, Giulia, Zuccato, Cristina, Finotti, Alessia, Lampronti, Ilaria, Borgatti, Monica, Chiavilli, Francesco, Gamberini, Maria Rita, Satta, Stefania, Manunza, Laura, De Martis, Franca Rosa, Moi, Paolo, Rivella, Stefano, Gambari, Roberto, and Bianchi, Nicoletta
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THALASSEMIA ,GENE therapy ,PHLEBOTOMISTS ,REPRODUCIBLE research ,ERYTHROCYTES ,MEDICAL research - Abstract
Background: Cellular biobanking is a key resource for collaborative networks planning to use same cells in studies aimed at solving a variety of biological and biomedical issues. This approach is of great importance in studies on β-thalassemia, since the recruitment of patients and collection of specimens can represent a crucial and often limiting factor in the experimental planning.Methods: Erythroid precursor cells were obtained from 72 patients, mostly β-thalassemic, expanded and cryopreserved. Expression of globin genes was analyzed by real time RT-qPCR. Hemoglobin production was studied by HPLC.Results: In this paper we describe the production and validation of a Thal-Biobank constituted by expanded erythroid precursor cells from β-thalassemia patients. The biobanked samples were validated for maintenance of their phenotype after (a) cell isolation from same patients during independent phlebotomies, (b) freezing step in different biobanked cryovials, (c) thawing step and analysis at different time points. Reproducibility was confirmed by shipping the frozen biobanked cells to different laboratories, where the cells were thawed, cultured and analyzed using the same standardized procedures. The biobanked cells were stratified on the basis of their baseline level of fetal hemoglobin production and exposed to fetal hemoglobin inducers.Conclusion: The use of biobanked cells allows stratification of the patients with respect to fetal hemoglobin production and can be used for determining the response to the fetal hemoglobin inducer hydroxyurea and to gene therapy protocols with reproducible results. [ABSTRACT FROM AUTHOR]- Published
- 2016
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6. Recent trends in the gene therapy of β-thalassemia.
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Finotti, Alessia, Bianchi, Nicoletta, Zuccato, Cristina, Gambari, Roberto, Breda, Laura, Rivella, Stefano, Lederer, Carsten W., and Kleanthous, Marina
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THALASSEMIA ,GLOBIN genes ,FETAL hemoglobin ,TRANSCRIPTION factors ,INDUCED pluripotent stem cells ,GENOME editing ,GENE therapy - Abstract
The β-thalassemias are a group of hereditary hematological diseases caused by over 300 mutations of the adult β-globin gene. Together with sickle cell anemia, thalassemia syndromes are among the most impactful diseases in developing countries, in which the lack of genetic counseling and prenatal diagnosis have contributed to the maintenance of a very high frequency of these genetic diseases in the population. Gene therapy for β-thalassemia has recently seen steadily accelerating progress and has reached a crossroads in its development. Presently, data from past and ongoing clinical trials guide the design of further clinical and preclinical studies based on gene augmentation, while fundamental insights into globin switching and new technology developments have inspired the investigation of novel gene-therapy approaches. Moreover, human erythropoietic stem cells from β-thalassemia patients have been the cellular targets of choice to date whereas future gene-therapy studies might increasingly draw on induced pluripotent stem cells. Herein, we summarize the most significant developments in β-thalassemia gene therapy over the last decade, with a strong emphasis on the most recent findings, for β-thalassemia model systems; for β-, γ-, and anti-sickling β-globin gene addition and combinatorial approaches including the latest results of clinical trials; and for novel approaches, such as transgene-mediated activation of γ-globin and genome editing using designer nucleases. [ABSTRACT FROM AUTHOR]
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- 2015
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7. A preclinical approach for gene therapy of β-thalassemia.
- Author
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Breda, Laura, Kleinert, Dorothy A., Casu, Carla, Casula, Laura, Cartegni, Luca, Fibach, Eitan, Mancini, Irene, Giardina, Patricia J., Gambari, Roberto, and Rivella, Stefano
- Subjects
THALASSEMIA ,GENE therapy ,PHENOTYPES ,LENTIVIRUSES ,CLINICAL trials - Abstract
Lentiviral-mediated β-globin gene transfer successfully treated β-thalassemic mice. Based on this result, clinical trials were initiated. To date, however, no study has investigated the efficacy of gene therapy in relation to the nature of the different β-globin mutations found in patients. Most mutations can be classified as β
0 or β+ , based on the amount of β-globin protein produced. Therefore, we propose that a screening in vitro is necessary to verify the efficacy of gene transfer prior to treatment of individual patients. We used a two-phase liquid culture system to expand and differentiate erythroid progenitor cells (ErPCs) transduced with lentiviral vectors. We propose the use of this system to test the efficiency of lentiviral vectors carrying the human β-globin gene, to correct the phenotype of ErPCs from patients preparing for gene therapy. This new approach might have profound implications for designing gene therapy and for understanding the genotype/phenotype variability observed in Cooley's anemia patients. [ABSTRACT FROM AUTHOR]- Published
- 2010
- Full Text
- View/download PDF
8. Progress Toward the Genetic Treatment of the β- Thalassemias.
- Author
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SADELAIN, MICHEL, LISOWSKI, LESZEK, SAMAKOGLU, SELDA, RIVELLA, STEFANO, MAY, CHAD, and RIVIERE, ISABELLE
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THALASSEMIA ,GENE therapy ,GLOBIN genes ,HEMOLYTIC anemia ,HEMATOPOIETIC stem cell transplantation ,ANEMIA - Abstract
The β-thalassemias are congenital anemias that are caused by mutations that reduce or abolish expression of the β-globin gene. They can be cured by allogeneic hematopoietic stem cell (HSC) transplantation, but this therapeutic option is not available to most patients. The transfer of a regulated β-globin gene in autologous HSCs is a highly attractive alternative treatment. This strategy, which is simple in principle, raises major challenges in terms of controlling expression of the globin transgene, which ideally should be erythroid specific, differentiationand stage-restricted, elevated, position independent, and sustained over time. Using lentiviral vectors, May et al. demonstrated in 2000 that an optimized combination of proximal and distal transcriptional control elements permits lineage-specific and elevated β-globin expression, resulting in therapeutic hemoglobin production and correction of anemia in thalassemic mice. Several groups have by now replicated and extended these findings to various mouse models of severe hemoglobinopathies, thus fueling enthusiasm for a potential treatment of β-thalassemia based on globin gene transfer. Current investigation focuses on safety issues and the need for improved vector production methodologies. The safe implementation of stem cell-based gene therapy requires the prevention of the formation of replication competent viral genomes and minimization of the risk of insertional oncogenesis. Importantly, globin vectors, in which transcriptional activity is highly restricted, have a lesser risk of activating oncogenes in hematopoietic progenitors than non-tissue-specific vectors, by virtue of their late-stage erythroid specificity. As such, they provide a general paradigm for improving vector safety in stem cell-based gene therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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9. Globin gene transfer: a paradigm for transgene regulation and vector safety.
- Author
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Rivella, Stefano, Lisowski, Leszek, and Sadelain, Michel
- Subjects
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THALASSEMIA , *SICKLE cell anemia , *STEM cells , *GENE therapy , *MUTAGENESIS - Abstract
The β-thalassemias and sickle cell disease are severe congenital anemias that are caused by the defective synthesis of the β chain of hemoglobin. Allogeneic hematopoietic stem cell (HSC) transplantation is curative, but this therapeutic option is not available to the majority of patients. The transfer of a regulated β-globin gene in autologous HCSs thus represents a highly attractive alternative treatment. This strategy, simple in principle, raises major challenges in terms of controlling transgene expression, which ideally should be erythroid-specific, differentiation stage-restricted, elevated, position-independent, and sustained over time. Using lentiviral vectors, we recently demonstrated that an optimized combination of proximal and distal transcriptional control elements permits lineage-specific and elevated expression of the β-globin gene, resulting in therapeutic hemoglobin production and correction of anemia in β-thalassemic mice. Several groups have now confirmed and extended these findings in various mouse models of severe hemoglobinopathies, thus generating enthusiasm for a genetic treatment based on globin gene transfer. Furthermore, globin vectors provide a paradigm for improving vector safety by restricting transgene expression to the differentiated progeny within a single lineage, thereby reducing the risk of activating oncogenes in hematopoietic progenitors. Here we review the principles underlying the genesis of regulated vectors for stem cell therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2003
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10. Emergent treatments for β-thalassemia and orphan drug legislations.
- Author
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Costa, Enrico, Cappellini, Maria Domenica, Rivella, Stefano, Chilin, Adriana, Alessi, Eva, Riccaboni, Massimo, Leufkens, Hubert G.M., and Luzzatto, Lucio
- Subjects
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ORPHAN drugs , *THERAPEUTICS , *FETAL hemoglobin , *RARE diseases , *GENE therapy , *BETA-Thalassemia - Abstract
• β-THAL is one of the most prevalent blood disorders in some regions of the world. • However, given its prevalence, in the EU and the US it is classified as a rare disease. • A wide array of therapeutic approaches has been developed over the past decades. • β-THAL is a learning case on the potential global impact of Orphan Legislations. • Gene therapy for β-THAL is promising, but scenarios for global access are missing. In many countries, β-thalassemia (β-THAL) is not uncommon; however, it qualifies as a rare disease in the US and in European Union (EU), where thalassemia drugs are eligible for Orphan Drug Designation (ODD). In this paper, we evaluate all 28 ODDs for β-THAL granted since 2001 in the US and the EU: of these, ten have since been discontinued, twelve are pending, and six have become licensed drugs available for clinical use. The prime mover for these advances has been the increasing depth of understanding of the pathophysiology of β-THAL; at the same time, and even though only one-fifth of β-THAL ODDs have become licensed drugs, the ODD legislation has clearly contributed substantially to the development of improved treatments for β-THAL. [ABSTRACT FROM AUTHOR]
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- 2022
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11. Single vs. dual transgene ex vivo gene therapy for multiple sulfatase deficiency.
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Pham, Vi, Tricoli, Lucas, Wongkittichote, Parith, Hong, Xinying, Schlotawa, Lars, Rivella, Stefano, and Ahrens-Nicklas, Rebecca
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SULFATASES , *GENE therapy - Published
- 2024
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12. Optimizing cross-correction to overcome limitations of ex vivo gene therapy in multiple sulfatase deficiency.
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Pham, Vi, Tricoli, Lucas, Schlotawa, Lars, Rivella, Stefano, and Ahrens-Nicklas, Rebecca
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GENE therapy , *SULFATASES - Published
- 2023
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13. In VivoGene Transfer Strategies to Achieve Partial Correction of von Willebrand Disease.
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Wang, Lan, Rosenberg, Jonathan B., De, Bishnu P., Ferris, Barbara, Wang, Rui, Rivella, Stefano, Kaminsky, Stephen M., and Crystal, Ronald G.
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GENETIC transformation , *VON Willebrand disease , *BLOOD coagulation disorders , *GENETIC disorders , *GENETIC mutation , *ANTISENSE DNA , *PLASMIDS , *MESSENGER RNA , *GENE therapy - Abstract
Abstractvon Willebrand disease (VWD), the most common hereditary coagulation disorder, results from mutations in the 52-exon gene for von Willebrand factor (VWF), which encodes an 8.4-kB cDNA. Studies with VWF cDNA plasmids have demonstrated that in vivogene transfer to the liver will correct the coagulation dysfunction in VWF−/−mice, but the correction is transient. To develop gene therapy for VWF that would mediate long-term expression of the VWF cDNA in liver, we first evaluated segmental pre-mRNA trans-splicing (SPTS) with two adeno-associated virus (AAV) serotype 8 vectors, each delivering one-half of the VWF cDNA. However, although the two vectors functioned well to generate VWF multimers after infection of cells in vitro, the efficiency of SPTS was insufficient to correct the VWF−/−mouse in vivo. As an alternative, we assessed the ability of a lentiviral vector to transfer the intact murine VWF cDNA in vivodirectly to the neonatal liver of VWF−/−mice, using generation of VWF multimers, bleeding time, and bleeding volume as efficacy parameters. The VWF lentivirus generated VWF multimers and partially or completely corrected the coagulation defect on a persistent basis in 33% of the treated VWF-deficient mice. On the basis of the concept that partial persistent correction with gene transfer could be beneficial in VWD patients, these observations suggest that lentiviral delivery of VWF cDNA should be explored as a candidate for gene therapy in patients with a severe form of VWD. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
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