scholarly journals NEW THERAPEUTIC OPTIONS FOR THE TREATMENT OF SICKLE CELL DISEASE

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Alessandro Matte ◽  
Filippo Mazzi ◽  
Enrica Federti ◽  
Oliviero Olivieri ◽  
Lucia De Franceschi
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Therapeutic Strategies ◽  
Therapeutic Options ◽  
High Morbidity ◽  
Novel Therapies ◽  
Cell Disease ◽  
Hematopoietic Stem ◽  
Positive Effects ◽  
Cell Dehydration

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. The pathophysiology related novel therapies are: a) Agents which reduce sickling or prevent sickle red cell dehydration; b) Agents targeting SCD vasculopathy and sickle cell-endothelial adhesive events; c) Anti-oxidant agents. This review highlights new therapeutic strategies in SCD and discusses future developments, research implications, and possible innovative clinical trials.  

Advances in Sickle Cell Disease Treatments

2020 ◽  
Vol 27 ◽  
Author(s):  
Aline Renata Pavan ◽  
Jean Leandro dos Santos
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Low Income ◽  
New Drugs ◽  
Low Income Countries ◽  
High Morbidity ◽  
Single Mutation ◽  
Cell Disease ◽  
Hematopoietic Stem ◽  
Therapeutic Alternatives

: Sickle Cell Disease (SCD) is an inherited disorder of red blood cells that is caused by a single mutation in the βglobin gene. The disease, which afflicts millions of patients worldwide mainly in low income countries, is characterized by high morbidity, mortality and low life expectancy. The new pharmacological and non-pharmacological strategies for SCD is urgent in order to promote treatments able to reduce patient’s suffering and improve their quality of life. Since the FDA approval of HU in 1998, there have been few advances in discovering new drugs; however, in the last three years voxelotor, crizanlizumab, and glutamine have been approved as new therapeutic alternatives. In addition, new promising compounds have been described to treat the main SCD symptoms. Herein, focusing on drug discovery, we discuss new strategies to treat SCD that have been carried out in the last ten years to discover new, safe, and effective treatments. Moreover, nonpharmacological approaches, including red blood cell exchange, gene therapy and hematopoietic stem cell transplantation will be presented.

scholarly journals New Therapeutic Options: Alternates to Gene Therapy for Treating Hemoglobinopathies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. SCI-49-SCI-49
Author(s):  
Lucia De Franceschi
Keyword(s):  
Gene Therapy ◽  
Sickle Cell ◽  
Iron Chelation ◽  
Organ Damage ◽  
Therapeutic Strategies ◽  
Therapeutic Options ◽  
Red Cell ◽  
Novel Therapies ◽  
Ineffective Erythropoiesis ◽  
Hematopoietic Stem

Hemoglobinopathies are chronic, invalidating globally distributed hereditary red cell disorders, which impact patient survival and quality of life. Sickle cell disease (SCD) and β-thalassemias are the more frequent hemoglobinopathies worldwide. In both SCD and β-thalassemias, novel therapeutic strategies might be divided into (1) pathophysiology related therapies and (2) innovative curative therapeuties such as hematopoietic stem cell transplantation and gene therapy, the latter discussed in another presentation in this session. In the last two decades, studies have highlighted the biocomplexity of SCD and β-thalassemias and the need for the development of new therapeutic options targeting one or more of the mechanisms involved in their pathogenesis. In SCD, the pathophysiology related novel therapies might be divided into: (i)Molecules targeting sickling and red cell dehydration; (ii) Molecules targeting SCD vasculopathy and sickle cell-endothelial adhesive events; (iii) Molecules modulating SCD related oxidative stress. Since inflammatory vasculopathy is a key factor in SCD related organ damage, major efforts have been made to develop agents that interfere with SCD vasculopathy and adhesion events, involving sickle red cells, neutrophils and endothelial interplay. β-thalassemic syndromes are characterized by ineffective erythropoiesis, which plays a crucial role in anemia and in the development of extramedullar erythropoiesis. In β-thalassemic syndromes, pathophysiology related novel therapies might be divided into: (i) Agents reducing the ineffective erythropoiesis such the TRAP ligands, targeting the GDF11 pathway (sotatercept or luspatercept); (ii) Agents affecting Jak2 activation to reduce splenomegaly in β-thalassemia and (iii) Agents modulating hepcidin - erythropoiesis axis such as minihepcidins. The main goal of these molecules is to ameliorate the ineffective erythropoiesis resulting in increased hemoglobin levels with reduction of transfusion requirement, iron overload, and facilitating iron chelation therapy. This review highlights new therapeutic strategies in SCD and β-thalassemia and discusses future development, research implications, and possible directions toward future clinical trials. Disclosures De Franceschi: F. Hoffmann-La Roche Ltd, Basel, Switzerland: Research Funding.

scholarly journals RH genotyping in a sickle cell disease patient contributing to hematopoietic stem cell transplantation donor selection and management

Blood ◽  
2010 ◽  
Vol 116 (15) ◽  
pp. 2836-2838 ◽  
Author(s):  
Ross M. Fasano ◽  
Alessandro Monaco ◽  
Emily Riehm Meier ◽  
Philippe Pary ◽  
A. Hallie Lee-Stroka ◽  
...  
Keyword(s):  
Stem Cell ◽  
Sickle Cell Disease ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Blood Group ◽  
Sickle Cell ◽  
Disease Patient ◽  
Nucleotide Sequencing ◽  
Cell Disease ◽  
Hematopoietic Stem

Abstract African individuals harbor molecular RH variants, which permit alloantibody formation to high-prevalence Rh antigens after transfusions. Genotyping identifies such RH variants, which are often missed by serologic blood group typing. Comprehensive molecular blood group analysis using 3 genotyping platforms, nucleotide sequencing, and serologic evaluation was performed on a 7-year-old African male with sickle cell disease who developed an “e-like” antibody shortly after initiating monthly red blood cell (RBC) transfusions for silent stroke. Genotyping of the RH variant predicted a severe shortage of compatible RBCs for long-term transfusion support, which contributed to the decision for hematopoetic stem cell transplantation. RH genotyping confirmed the RH variant in the human leukocyte antigen–matched sibling donor. The patient's (C)ces type 1 haplotype occurs in up to 11% of African American sickle cell disease patients; however, haplotype-matched RBCs were serologically incompatible. This case documents that blood unit selection should be based on genotype rather than one matching haplotype.

Demands and challenges for patients with sickle-cell disease requiring hematopoietic stem cell transplantation in Saudi Arabia

2016 ◽  
Vol 20 (6) ◽  
pp. 831-835 ◽  
Author(s):  
Abdulrahman Alsultan ◽  
Wasil Jastaniah ◽  
Sameera Al Afghani ◽  
Muneer H. Al Bagshi ◽  
Zaki Nasserullah ◽  
...  
Keyword(s):  
Saudi Arabia ◽  
Stem Cell ◽  
Sickle Cell Disease ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Sickle Cell ◽  
Cell Disease ◽  
Hematopoietic Stem

scholarly journals 115. Correction of the Sickle-Cell Disease Mutation in Human Hematopoietic Stem/Progenitor Cells

2015 ◽  
Vol 23 ◽  
pp. S48
Author(s):  
Megan D. Hoban ◽  
Matthew C. Mendel ◽  
Zulema Romero ◽  
Michael L. Kaufman ◽  
Alok V. Joglekar ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Progenitor Cells ◽  
Sickle Cell ◽  
Cell Disease ◽  
Hematopoietic Stem ◽  
Disease Mutation

Sickle Cell Disease Hematopoietic Stem Cell gene therapy with globin gene addition is promising

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Gene Therapy ◽  
Stem Cell ◽  
Sickle Cell Disease ◽  
Hematopoietic Stem Cell ◽  
Sickle Cell ◽  
Globin Gene ◽  
Autologous Transplantation ◽  
Gene Repair ◽  
Cell Disease ◽  
Hematopoietic Stem

Autologous transplantation of gene-modified HSCs might be used to treat Sickle Cell Disease (SCD) once and for all. Hematopoietic Stem Cell (HSC) gene therapy with lentiviral-globin gene addition was optimized by HSC collection, vector constructs, lentiviral transduction, and conditioning in the current gene therapy experiment for SCD, resulting in higher gene marking and phenotypic correction. Further advancements over the next decade should allow for a widely approved gene-addition therapy. Long-term engraftment is crucial for gene-corrected CD34+ HSCs, which might be addressed in the coming years, and gene repair of the SCD mutation in the-globin gene can be achieved in vitro using genome editing in CD34+ cells. Because of breakthroughs in efficacy, safety, and delivery strategies, in vivo gene addition and gene correction in BM HSCs is advancing. Overall, further research is needed, but HSC-targeted gene addition/gene editing therapy is a promising SCD therapy with curative potential that might be widely available soon.

scholarly journals Early Myeloid Derived Suppressor Cells (eMDSCs) Are Associated With High Donor Myeloid Chimerism Following Haploidentical HSCT for Sickle Cell Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Deepali K. Bhat ◽  
Purevdorj B. Olkhanud ◽  
Arunakumar Gangaplara ◽  
Fayaz Seifuddin ◽  
Mehdi Pirooznia ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Graft Rejection ◽  
Immune Cell ◽  
Plasma Concentrations ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
Cell Disease ◽  
Hematopoietic Stem ◽  
Post Transplant

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is a widely available curative option for patients with sickle cell disease (SCD). Our original non-myeloablative haplo-HSCT trial employing post-transplant (PT) cyclophosphamide had a low incidence of GVHD but had high rejection rates. Here, we aimed to evaluate immune reconstitution following haplo-HSCT and identify cytokines and cells associated with graft rejection/engraftment. 50 cytokines and 10 immune cell subsets were screened using multiplex-ELISA and flow cytometry, respectively, at baseline and PT-Days 30, 60, 100, and 180. We observed the most significant differences in cytokine levels between the engrafted and rejected groups at PT-Day 60, corresponding with clinical findings of secondary graft rejection. Of the 44 cytokines evaluated, plasma concentrations of 19 cytokines were different between the two groups at PT-Day 60. Factor analysis suggested two independent factors. The first factor (IL-17A, IL-10, IL-7, G-CSF, IL-2, MIP-1a, VEGF, and TGFb1 contributed significantly) was strongly associated with engraftment with OR = 2.7 (95%CI of 1.4 to 5.4), whereas the second factor (GROa and IL-18 contributed significantly) was not significantly associated with engraftment. Sufficient donor myeloid chimerism (DMC) is critical for the success of HSCT; here, we evaluated immune cells among high (H) DMC (DMC≥20%) and low (L) DMC (DMC<20%) groups along with engrafted and rejected groups. We found that early myeloid-derived suppressor cell (eMDSC) frequencies were elevated in engrafted patients and patients with HDMC at PT-Day 30 (P< 0.04 & P< 0.003, respectively). 9 of 20 patients were evaluated for the source of eMDSCs. The HDMC group had high mixed chimeric eMDSCs as compared to the LDMC group (P< 0.00001). We found a positive correlation between the frequencies of eMDSCs and Tregs at PT-Day 100 (r=0.72, P <0.0007); eMDSCs at BSL and Tregs at PT-Day 100 (r=0.63, P <0.004). Of 10 immune regulatory cells and 50 cytokines, we observed mixed chimeric eMDSCs and IL-17A, IL-10, IL-7, G-CSF, IL-2, MIP-1a, VEGF, TGFb1 as potential hits which could serve as prognostic markers in predicting allograft outcome towards engraftment following haploidentical HSCT employing post-transplant cyclophosphamide. The current findings need to be replicated and further explored in a larger cohort.

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