Correction of Sickle Cell Disease in Transgenic Mouse Models by Gene Therapy

@article{Pawliuk2001CorrectionOS,
  title={Correction of Sickle Cell Disease in Transgenic Mouse Models by Gene Therapy},
  author={Robert Pawliuk and Karen A. Westerman and Mary E. Fabry and Emmanuel Payen and Robert Tighe and Eric E. Bouhassira and Seetharama A. Acharya and James Ellis and Irving M. London and Connie J. Eaves and R. Keith Humphries and Yves Beuzard and Ronald L. Nagel and Philippe Leboulch},
  journal={Science},
  year={2001},
  volume={294},
  pages={2368 - 2371}
}
Sickle cell disease (SCD) is caused by a single point mutation in the human βA globin gene that results in the formation of an abnormal hemoglobin [HbS (α2βS 2)]. We designed a βA globin gene variant that prevents HbS polymerization and introduced it into a lentiviral vector we optimized for transfer to hematopoietic stem cells and gene expression in the adult red blood cell lineage. Long-term expression (up to 10 months) was achieved, without preselection, in all transplanted mice with… 
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Proof-of-principle studies provide a foundation for the development of gene replacement therapy for human patients with SCD and other blood disorders.
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The data in this paper demonstrate that sickle cell disease can be corrected without the risk of insertional mutagenesis and provide a foundation for similar studies in human ES cells derived from sickle Cell patients.
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    The New England journal of medicine
  • 2017
TLDR
First patient treated with lentiviral vector–mediated addition of an antisickling β-globin gene into autologous hematopoietic stem cells without recurrence of sickle crises and with correction of the biologic hallmarks of the disease is described.
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This study provides a comprehensive in vitro and in vivo analysis of two globin lentiviral vectors, which is useful for determining the optimal candidate for SCD gene therapy.
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It is demonstrated that inactivation of BCL11A in SCD transgenic mice corrects the hematologic and pathologic defects associated with SCD through high-level pancellular HbF induction.
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First patient treated with lentiviral vector–mediated addition of an antisickling β‐globin gene into autologous hematopoietic stem cells without recurrence of sickle crises and with correction of the biologic hallmarks of the disease is described.
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    AAP Grand Rounds
  • 2022
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Gene therapy strategies specific to Sickle cell disease are discussed, the present state of the field, and current status of the gene therapy clinical trials are discussed.
A novel human gamma-globin gene vector for genetic correction of sickle cell anemia in a humanized sickle mouse model: critical determinants for successful correction.
TLDR
These studies provide a strong preclinical model for what it would take to genetically correct sickle cell anemia (SCA) and are a foundation for the use of this vector in a human clinical trial.
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The molecular and Biological properties of the Human Immunodeficiency Virus Viral Pathogenesis of Hematological Disorders B19 Parvoviruses HTLVs Herpesviruses and the Gene Therapy of Hemopoietic Diseases are studied.