scholarly journals Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease

Blood ◽  
2016 ◽  
Vol 127 (7) ◽  
pp. 839-848 ◽  
Author(s):  
Megan D. Hoban ◽  
Stuart H. Orkin ◽  
Daniel E. Bauer
Keyword(s):  
Gene Therapy ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Genome Engineering ◽  
Genetic Manipulation ◽  
Clinical Success ◽  
Retroviral Vectors ◽  
Globin Genes ◽  
Cell Disease ◽  
Gene Therapies

AbstractEffective medical management for sickle cell disease (SCD) remains elusive. As a prevalent and severe monogenic disorder, SCD has been long considered a logical candidate for gene therapy. Significant progress has been made in moving toward this goal. These efforts have provided substantial insight into the natural regulation of the globin genes and illuminated challenges for genetic manipulation of the hematopoietic system. The initial γ-retroviral vectors, next-generation lentiviral vectors, and novel genome engineering and gene regulation approaches each share the goal of preventing erythrocyte sickling. After years of preclinical studies, several clinical trials for SCD gene therapies are now open. This review focuses on progress made toward achieving gene therapy, the current state of the field, consideration of factors that may determine clinical success, and prospects for future development.

Major Challenges for Gene Therapy of Thalassemia and Sickle Cell Disease

2010 ◽  
Vol 10 (5) ◽  
pp. 404-412 ◽  
Author(s):  
Eleni Papanikolaou ◽  
Nicholas P. Anagnou
Keyword(s):  
Gene Therapy ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Disease

scholarly journals Resolution of Serious Vaso-Occlusive Pain Crises: Results from the Ongoing Phase 1/2 HGB-206 Group C Study of LentiGlobin for Sickle Cell Disease (SCD; bb1111) Gene Therapy

2021 ◽  
Vol 27 (3) ◽  
pp. S12-S13
Author(s):  
Mark C. Walters ◽  
Alexis A. Thompson ◽  
Markus Y. Mapara ◽  
Janet L. Kwiatkowski ◽  
Lakshmanan Krishnamurti ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Phase 1 ◽  
Cell Disease ◽  
Ongoing Phase

scholarly journals Gene therapy: Erasing sickle-cell disease

Nature ◽  
2017 ◽  
Vol 549 (7673) ◽  
pp. S28-S30 ◽  
Author(s):  
Katherine Bourzac
Keyword(s):  
Gene Therapy ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Disease

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 Engineering, Generation and Preliminary Characterization of a Humanized Porcine Sickle Cell Disease Animal Model

2020 ◽  
Author(s):  
Tobias M. Franks ◽  
Sharie J. Haugabook ◽  
Elizabeth A. Ottinger ◽  
Meghan S. Vermillion ◽  
Kevin M. Pawlik ◽  
...  
Keyword(s):  
Animal Model ◽  
Sickle Cell Disease ◽  
Mouse Models ◽  
Sickle Cell ◽  
Cell Model ◽  
Globin Genes ◽  
Cell Disease ◽  
Small Vessels

AbstractMouse models of sickle cell disease (SCD) that faithfully switch from fetal to adult hemoglobin (Hb) have been important research tools that accelerated advancement towards treatments and cures for SCD. Red blood cells (RBCs) in these animals sickled in vivo, occluded small vessels in many organs and resulted in severe anemia like in human patients. SCD mouse models have been valuable in advancing clinical translation of some therapeutics and providing a better understanding of the pathophysiology of SCD. However, mouse models vary greatly from humans in their anatomy and physiology and therefore have limited application for certain translational efforts to transition from the bench to bedside. These differences create the need for a higher order animal model to continue the advancement of efforts in not only understanding relevant underlying pathophysiology, but also the translational aspects necessary for the development of better therapeutics to treat or cure SCD. Here we describe the development of a humanized porcine sickle cell model that like the SCD mice, expresses human ɑ-, β− and γ-globin genes under the control of the respective endogenous porcine locus control regions (LCR). We also describe our initial characterization of the SCD pigs and plans to make this model available to the broader research community.

Leukemia after gene therapy for sickle cell disease: insertional mutagenesis, busulfan, both or neither

Blood ◽  
2021 ◽  
Author(s):  
Rick J. Jones ◽  
Michael R DeBaun
Keyword(s):  
Gene Therapy ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Insertional Mutagenesis ◽  
Absolute Risk ◽  
Cell Disease ◽  
Post Transplantation ◽  
Curative Therapy ◽  
Gene Therapy Trial ◽  
Safe Strategy

Recently, encouraging data provided long-awaited hope for gene therapy as a cure for sickle cell disease (SCD). Nevertheless, the suspension of the bluebird bio gene therapy trial (ClinicalTrials.gov: NCT02140554) after participants developed acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) is concerning. Potential possibilities for these cases include busulfan, insertional mutagenesis, both or neither. Busulfan was considered the cause in the first reported case, as the transgene was not present in the AML/MDS. However, busulfan is unlikely to have contributed to the most recent case. The transgene was present in the patient's malignant cells, indicating they were infused after busulfan treatment. Several lines of evidence suggest an alternative explanation for events in the bluebird bio trial, including that SCD population studies show an increased relative, but a low absolute, risk of AML/MDS. We propose a new hypothesis: after gene therapy for SCD, the stress of switching from homeostatic to regenerative hematopoiesis by transplanted cells drives clonal expansion and leukemogenic transformation of pre-existing premalignant clones, eventually resulting in AML/MDS. Evidence validating our hypothesis will support pre-screening individuals with SCD for pre-leukemic progenitors before gene therapy. Until a viable, safe strategy has been implemented to resume gene therapy in adults with severe SCD, reasonable alternative curative therapy should be considered for children and adults with severe SCD. Currently, open multi-center clinical trials are incorporating nonmyeloablative conditioning, related haploidentical donors, and post-transplantation cyclophosphamide. Preliminary results from these trials appear promising and NIH-sponsored trials are ongoing in pediatric and adult individuals with SCD using this platform.

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