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stem cell transplant in SCD

Gregory M T Guilcher, Dania A Monagel, Alberto Nettel-Aguirre, Tony H Truong, Sunil J Desai, Aisha Bruce, Ravi M Shah, Michael T Leaker, Victor A Lewis
Sickle cell disease (SCD) is a potentially debilitating hemoglobinopathy associated with early mortality. The only established curative therapy is hematopoietic cell transplantation (HCT)with a matched sibling donor (MSD). The National Institutes of Health (NIH) nonmyeloablative regimen of alemtuzumab/300 cGy total body irradiation and prolonged sirolimus exposure for graft-versus-host disease (GVHD) prophylaxis was administered to 16 children and adolescents. Infused products were unmanipulated G-CSF mobilized peripheral blood stem cells...
February 14, 2019: Biology of Blood and Marrow Transplantation
Christopher T Lux, Sowmya Pattabhi, Mason Berger, Cynthia Nourigat, David A Flowers, Olivier Negre, Olivier Humbert, Julia G Yang, Calvin Lee, Kyle Jacoby, Irwin Bernstein, Hans-Peter Kiem, Andrew Scharenberg, David J Rawlings
Elements within the γ-hemoglobin promoters ( HBG1 and HBG2 ) function to bind transcription complexes that mediate repression of fetal hemoglobin expression. Sickle cell disease (SCD) subjects with a 13-bp deletion in the HBG1 promoter exhibit a clinically favorable hereditary persistence of fetal hemoglobin (HPFH) phenotype. We developed TALENs targeting the homologous HBG promoters to de-repress fetal hemoglobin. Transfection of human CD34+ cells with TALEN mRNA resulted in indel generation in HBG1 (43%) and HBG2 (74%) including the 13-bp HPFH deletion (∼6%)...
March 15, 2019: Molecular Therapy. Methods & Clinical Development
Valentina Ghiaccio, Maxwell Chappell, Stefano Rivella, Laura Breda
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...
January 30, 2019: Molecular Diagnosis & Therapy
Nicola Conran, Lidiane Torres
Sickle cell disease (SCD) is one of the most common inherited diseases and is associated with a reduced life expectancy and acute and chronic complications, including frequent painful vaso-occlusive episodes that often require hospitalization. At present, treatment of SCD is limited to hematopoietic stem cell transplant, transfusion, and limited options for pharmacotherapy, based principally on hydroxyurea therapy. This review highlights the importance of intracellular cGMP-dependent signaling pathways in SCD pathophysiology; modulation of these pathways with soluble guanylate cyclase (sGC) stimulators or phosphodiesterase (PDE) inhibitors could potentially provide vasorelaxation and anti-inflammatory effects, as well as elevate levels of anti-sickling fetal hemoglobin...
January 28, 2019: Experimental Biology and Medicine
Alessandro Matte, Francesco Zorzi, Filippo Mazzi, Enrica Federti, Oliviero Olivieri, Lucia De Franceschi
Sickle cell disease (SCD; ORPHA232; OMIM # 603903) is a chronic and invalidating disorder distributed worldwide, with high morbidity and mortality. Given the disease complexity and the multiplicity of pathophysiological targets, development of new therapeutic options is critical, despite the positive effects of hydroxyurea (HU), for many years the only approved drug for SCD. New therapeutic strategies might be divided into (1) pathophysiology-related novel therapies and (2) innovations in curative therapeutic options such as hematopoietic stem cell transplantation and gene therapy...
2019: Mediterranean Journal of Hematology and Infectious Diseases
Rachael Davis, Aishwarya Gurumurthy, Mir A Hossain, Eliot M Gunn, Jörg Bungert
Hemoglobinopathies, including sickle cell disease and thalassemia, are among the most common inherited genetic diseases worldwide. Due to the relative ease of isolating and genetically modifying hematopoietic stem and progenitor cells, recent gene editing and gene therapy strategies have progressed to clinical trials with promising outcomes; however, challenges remain and necessitate the continued exploration of new gene engineering and cell transplantation protocols. Current gene engineering strategies aim at reactivating the expression of the fetal γ-globin genes in adult erythroid cells...
March 15, 2019: Molecular Therapy. Methods & Clinical Development
Donald B Kohn
Genetic diseases affecting proteins and cells composing the blood may be treated by gene therapy using gene addition or gene editing methods. Protein deficiencies (e.g. hemophilia) are being approached using in vivo gene delivery by adeno-associated virus (AAV) vectors for therapeutic gene addition or gene editing. Blood cell diseases (e.g. sickle cell disease) are being approached using ex vivo gene addition or gene editing to treat isolated blood-forming hematopoietic stem cells or T cells that are then re-transplanted...
December 29, 2018: Current Opinion in Biotechnology
Seung Jun Choi, Hanwool Cho, Ki-Seong Eom, Jong Wook Lee, Yonggoo Kim, Jihyang Lim
No abstract text is available yet for this article.
December 2018: Blood Research
Renée V Gardner
Background: Sickle cell disease causes significant morbidity and mortality and affects the economic and healthcare status of many countries. Yet historically, the disease has not had commensurate outlays of funds that have been aimed at research and development of drugs and treatment procedures for other diseases. Methods: This review examines several treatment modalities and new drugs developed since the late 1990s that have been used to improve outcomes for patients with sickle cell disease...
2018: Ochsner Journal
Valentina Poletti, Fabrizia Urbinati, Sabine Charrier, Guillaume Corre, Roger P Hollis, Beatriz Campo Fernandez, Samia Martin, Michael Rothe, Axel Schambach, Donald B Kohn, Fulvio Mavilio
Sickle cell disease (SCD) is caused by a mutation (E6V) in the hemoglobin (Hb) β-chain that induces polymerization of Hb tetramers, red blood cell deformation, ischemia, anemia, and multiple organ damage. Gene therapy is a potential alternative to human leukocyte antigen (HLA)-matched allogeneic hematopoietic stem cell transplantation, available to a minority of patients. We developed a lentiviral vector expressing a β-globin carrying three anti-sickling mutations (T87Q, G16D, and E22A) inhibiting axial and lateral contacts in the HbS polymer, under the control of the β-globin promoter and a reduced version of the β-globin locus-control region...
December 14, 2018: Molecular Therapy. Methods & Clinical Development
Leslie Weber, Valentina Poletti, Elisa Magrin, Chiara Antoniani, Samia Martin, Charles Bayard, Hanem Sadek, Tristan Felix, Vasco Meneghini, Michael N Antoniou, Wassim El-Nemer, Fulvio Mavilio, Marina Cavazzana, Isabelle Andre-Schmutz, Annarita Miccio
Autologous transplantation of hematopoietic stem cells transduced with a lentiviral vector (LV) expressing an anti-sickling HBB variant is a potential treatment for sickle cell disease (SCD). With a clinical trial as our ultimate goal, we generated LV constructs containing an anti-sickling HBB transgene ( HBBAS3 ), a minimal HBB promoter, and different combinations of DNase I hypersensitive sites (HSs) from the locus control region (LCR). Hematopoietic stem progenitor cells (HSPCs) from SCD patients were transduced with LVs containing either HS2 and HS3 (β-AS3) or HS2, HS3, and HS4 (β-AS3 HS4)...
September 21, 2018: Molecular Therapy. Methods & Clinical Development
Angela Rivers, Ramasamy Jagadeeswaran, Donald Lavelle
Sickle cell disease (SCD) is caused by a mutation of the b-globin gene(21) that triggers the polymerization of deoxygenated sickle hemoglobin (HbS). Approximately 100,000 SCD patients in the U.S. and millions worldwide(53) suffer from chronic hemolytic anemia, painful crises, multisystem organ damage, and reduced life expectancy(60, 70). Hematopoietic stem cell (HSC) transplantation can be curative, but the majority of patients do not have a suitable donor (80). Advanced gene editing technologies also offer the possibility of a cure (16, 34), but the likelihood that these strategies can be mobilized to treat the large numbers of patients residing in developing countries is remote...
August 1, 2018: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Laura Alonso, Marta González-Vicent, Cristina Belendez, Isabel Badell, Ana Sastre, Antonia Rodríguez-Villa, Mar Bermúdez-Cortés, Raquel Hladun, Cristina Díaz de Heredia
BACKGROUND AND OBJECTIVES: A recently occurring increase of the prevalence of haemoglobinopathies, β-thalassaemia major (TM) and sickle cell disease (SCD) over the last two decades in our country has generated new needs in terms of medical resources for both prevention and treatment of these patients. Allogeneic haematopoietic stem cell transplant (allo-HSCT) is a curative treatment available for patients who have severe haemoglobinopathies. The main objective of this study was to evaluate the results of allo-HSCT in paediatric patients with TM or SCD performed in paediatric hematopoietic transplant units within the Spanish Group of Bone Marrow Transplantation in Children (GETMON)...
July 9, 2018: Medicina Clínica
Bo-Kyoung Park, Hyo-Sup Kim, Seongkoo Kim, Jae-Wook Lee, Young Shil Park, Pil-Sang Jang, Nack-Gyun Chung, Dae-Chul Jeong, Bin Cho
Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for β-thalassemia major (TM) and sickle cell disease (SCD) in children. Graft-versus-host disease (GVHD) and treatment-related mortality (TRM) remain significant challenges to improving survival after HSCT. Here, we analyzed the outcome of TM and SCD patients, who received allogeneic HSCT with myeloablative conditioning at our institution. Methods: Twenty-two patients (15 TM, 7 SCD), with a median age of 9 years (range, 1...
June 2018: Blood Research
Erica B Esrick, Daniel E Bauer
After decades with few novel therapeutic options for sickle cell disease (SCD), autologous hematopoietic stem cell (HSC) based genetic therapies including lentiviral gene therapy (GT), and genome editing (GE) now appear imminent. Lentiviral GT has advanced considerably in the past decade with promising clinical trial results in multiple disorders. For β-hemoglobinopathies, GT strategies of gene addition and fetal hemoglobin induction through BCL11A regulation are both being evaluated in open clinical trials...
April 2018: Seminars in Hematology
Alexis Leonard, John F Tisdale
Sickle cell disease (SCD) is the most common inherited hemoglobinopathy worldwide, and is a life-limiting disease with limited therapeutic options to reduce disease severity. Despite being a monogenic disorder, the clinical phenotypes of SCD are variable, with few reliable predictors of disease severity easily identifying patients where the benefits of curative therapy outweigh the risks. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative option, though significant advances in gene therapy raise the promise for additional curative methods...
July 2018: Expert Review of Hematology
Selami Demirci, John F Tisdale
Derivation of functional and mature red blood cells (RBCs) with adult globin expression from renewable source such as induced pluripotent stem cells (iPSCs) is of importance from the clinical point of view. Definitive RBC generation can only be succeeded through production of true hematopoietic stem cells (HSCs). There has been a great effort to obtain definitive engraftable HSCs from iPSCs but the results were mostly unsatisfactory due to low, short-term and linage-biased engraftment in mouse models. Moreover, ex vivo differentiation approaches ended up with RBCs with mostly embryonic and fetal globin expression...
June 7, 2018: Advances in Experimental Medicine and Biology
Selami Demirci, Naoya Uchida, John F Tisdale
Sickle cell disease (SCD) is one of the most common life-threatening monogenic diseases affecting millions of people worldwide. Allogenic hematopietic stem cell transplantation is the only known cure for the disease with high success rates, but the limited availability of matched sibling donors and the high risk of transplantation-related side effects force the scientific community to envision additional therapies. Ex vivo gene therapy through globin gene addition has been investigated extensively and is currently being tested in clinical trials that have begun reporting encouraging data...
July 2018: Cytotherapy
Karine Sii-Felice, Marie Giorgi, Philippe Leboulch, Emmanuel Payen
The β-hemoglobinopathies, transfusion-dependent β-thalassemia and sickle cell disease, are the most prevalent inherited disorders worldwide and affect millions of people. Many of these patients have a shortened life expectancy and suffer from severe morbidity despite supportive therapies, which impose an enormous financial burden to societies. The only available curative therapy is allogeneic hematopoietic stem cell transplantation, although most patients do not have an HLA-matched sibling donor, and those who do still risk life-threatening complications...
August 2018: Experimental Hematology
Hafiz Muhammad Aslam, Said Yousuf, Adetola Kassim, Shumaila Muhammad Iqbal, Shahrukh K Hashmi
Current projections estimate that the number of newborns with sickle cell disease (SCD) globally will exceed 400,000 by 2050. Over the last three decades, increased newborn screening, supportive care, and use of hydroxyurea therapy, have decreased early childhood mortality among individuals affected with SCD. Despite hematopoietic cell transplantation (HCT) being curative in SCD, its impact on disease free survival remains unknown, especially in adults, partly due to previous limitations in donor options and perceived mortality in adults using myeloablative conditioning...
May 4, 2018: Bone Marrow Transplantation
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