TY - JOUR
TI - The New Self-Inactivating Lentiviral Vector for Thalassemia Gene Therapy
Combining Two HPFH Activating Elements Corrects Human Thalassemic
Hematopoietic Stem Cells
AU - Papanikolaou, Eleni
AU - Georgomanoli, Maria
AU - Stamateris, Evangelos
AU - and Panetsos, Fottes
AU - Karagiorga, Markisia
AU - Tsaftaridis,
AU - Panagiotis
AU - Graphakos, Stelios
AU - Anagnou, Nicholas P.
JO - Human Gene Therapy
PY - 2012
VL - 23
TODO - 1
SP - 15-31
PB - MARY ANN LIEBERT INC PUBL
SN - 1043-0342, 1557-7422
TODO - 10.1089/hum.2011.048
TODO - null
TODO - To address how low titer, variable expression, and gene silencing affect
gene therapy vectors for hemoglobinopathies, in a previous study we
successfully used the HPFH (hereditary persistence of fetal
hemoglobin)-2 enhancer in a series of oncoretroviral vectors. On the
basis of these data, we generated a novel insulated self-inactivating
(SIN) lentiviral vector, termed GGHI, carrying the (A)gamma-globin gene
with the -117 HPFH point mutation and the HPFH-2 enhancer and exhibiting
a pancellular pattern of (A)gamma-globin gene expression in MEL-585
clones. To assess the eventual clinical feasibility of this vector, GGHI
was tested on CD34(+) hematopoietic stem cells from nonmobilized
peripheral blood or bone marrow from 20 patients with beta-thalassemia.
Our results show that GGHI increased the production of gamma-globin by
32.9% as measured by high-performance liquid chromatography ( p=0.001),
with a mean vector copy number per cell of 1.1 and a mean transduction
efficiency of 40.3%. Transduced populations also exhibited a lower rate
of apoptosis and resulted in improvement of erythropoiesis with a higher
percentage of orthochromatic erythroblasts. This is the first report of
a locus control region (LCR)-free SIN insulated lentiviral vector that
can be used to efficiently produce the anticipated therapeutic levels of
gamma-globin protein in the erythroid progeny of primary human
thalassemic hematopoietic stem cells in vitro.
ER -