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.

Abstract	We show that lentiviral delivery of human gamma-globin gene under beta-globin regulatory control elements in hematopoietic stem cells (HSCs) results in sufficient postnatal fetal hemoglobin (HbF) expression to correct sickle cell anemia (SCA) in the Berkeley "humanized" sickle mouse. Upon de-escalating the amount of transduced HSCs in transplant recipients, using reduced-intensity conditioning and varying gene transfer efficiency and vector copy number, we assessed critical parameters needed for correction. A systematic quantification of functional and hematologic red blood cell (RBC) indices, organ pathology, and life span was used to determine the minimal amount of HbF, F cells, HbF/F-cell, and gene-modified HSCs required for correcting the sickle phenotype. We show that long-term amelioration of disease occurred (1) when HbF exceeded 10%, F cells constituted two-thirds of the circulating RBCs, and HbF/F cell was one-third of the total hemoglobin in sickle RBCs; and (2) when approximately 20% gene-modified HSCs repopulated the marrow. Moreover, we show a novel model using reduced-intensity conditioning to determine genetically corrected HSC threshold that corrects a hematopoietic disease. These studies provide a strong preclinical model for what it would take to genetically correct SCA and are a foundation for the use of this vector in a human clinical trial.
Authors	Ajay Perumbeti, Tomoyasu Higashimoto, Fabrizia Urbinati, Robert Franco, Herbert J Meiselman, David Witte, Punam Malik
Journal	Blood (Blood) Vol. 114 Issue 6 Pg. 1174-85 (Aug 06 2009) ISSN: 1528-0020 [Electronic] United States
PMID	19474450 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References	gamma-Globins Fetal Hemoglobin
Topics	Anemia, Sickle Cell (blood, genetics, therapy) Animals Disease Models, Animal Erythrocyte Indices Erythrocytes, Abnormal (metabolism) Fetal Hemoglobin (biosynthesis) Genetic Therapy Genetic Vectors Humans Mice Mice, SCID Regulatory Elements, Transcriptional gamma-Globins (biosynthesis, genetics)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!