CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia.

@article{Frangoul2020CRISPRCas9GE,
  title={CRISPR-Cas9 Gene Editing for Sickle Cell Disease and $\beta$-Thalassemia.},
  author={Haydar A. Frangoul and Dr. David Altshuler and Maria Domenica Cappellini and Yi-Shan Chen and Jennifer A. Domm and Brenda K. Eustace and Juergen L Foell and Josu de la Fuente and Stephan A. Grupp and Rupert Handgretinger and Tony W. Ho and Antonis Kattamis and Andrew Kernytsky and Julie A. Lekstrom‐Himes and Amanda M. Li and Franco Locatelli and Markus Y Mapara and Mariane de Montalembert and Damiano Rondelli and Akshay Sharma and Sujit Sheth and Sandeep Soni and Martin H. Steinberg and Donna A. Wall and Angela Yen and Selim Corbacioglu},
  journal={The New England journal of medicine},
  year={2020}
}
Transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) are severe monogenic diseases with severe and potentially life-threatening manifestations. BCL11A is a transcription factor that represses γ-globin expression and fetal hemoglobin in erythroid cells. We performed electroporation of CD34+ hematopoietic stem and progenitor cells obtained from healthy donors, with CRISPR-Cas9 targeting the BCL11A erythroid-specific enhancer. Approximately 80% of the alleles at this locus were… 

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References

SHOWING 1-10 OF 34 REFERENCES
Highly efficient therapeutic gene editing of human hematopoietic stem cells
TLDR
Optimized conditions for ribonucleoprotein delivery of Cas9–sgRNA complexes enables precise and efficient gene editing to restore fetal hemoglobin expression in sickle cell disease patient-derived HSCs.
Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease.
TLDR
This study validates BCL11A inhibition as an effective target for HbF induction and provides preliminary evidence that shmiR-based gene knockdown offers a favorable risk-benefit profile in sickle cell disease.
Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype.
TLDR
It is found that using optimized shRNAs embedded within an miRNA (shRNAmiR) architecture to achieve ubiquitous knockdown of BCL11A profoundly impaired long-term engraftment of both human and mouse hematopoietic stem cells (HSCs) despite a reduction in nonspecific cellular toxicities.
Preclinical Evaluation of a Novel Lentiviral Vector Driving Lineage-Specific BCL11A Knockdown for Sickle Cell Gene Therapy
TLDR
It is demonstrated that BCH-BB694 LVV is non-toxic and efficacious in preclinical studies, and can be generated at a clinically relevant scale in a GMP setting at high titer to support clinical testing for the treatment of SCD.
Gene Therapy in Patients with Transfusion‐Dependent β‐Thalassemia
TLDR
Gene therapy with autologous CD34+ cells transduced with the BB305 vector reduced or eliminated the need for long‐term red‐cell transfusions in 22 patients with severe β‐thalassemia without serious adverse events related to the drug product.
CRISPR/Cas9 genome editing in human hematopoietic stem cells.
TLDR
This protocol enables manipulation of genes for investigation of gene functions during hematopoiesis, as well as for the correction of genetic mutations in HSC transplantation-based therapies for diseases such as sickle cell disease, β-thalassemia, and primary immunodeficiencies.
Customizing the genome as therapy for the β-hemoglobinopathies.
TLDR
The use of genome-editing technologies in autologous CD34(+) hematopoietic stem and progenitor cells represents a promising therapeutic avenue for the β-globin disorders.
Differences in the clinical and genotypic presentation of sickle cell disease around the world.
TLDR
Hb SS, absence of co-inheriting alpha-thalassemia, and low hemoglobin F levels tend to be associated with more hemolysis, lower hemoglobin oxygen saturations, greater proportions of elevated tricuspid regurgitant jet velocity and brain natriuretic peptide, and increased left ventricular mass index.
Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of β-thalassemia
TLDR
It is indicated that BCL11A variants, by modulating HbF levels, act as an important ameliorating factor of the β-thalassemia phenotype, and it is likely they could helpAmeliorate other hemoglobin disorders.
Fetal hemoglobin in sickle cell anemia.
TLDR
New efforts to induce high HbF levels in sickle cell disease beyond those achievable with the current limited repertory of Hbf inducers are spurred on.
...
1
2
3
4
...