Τίτλος:
A Novel BaEVRless-Pseudotyped gamma-Globin Lentiviral Vector Drives High
and Stable Fetal Hemoglobin Expression and Improves Thalassemic
Erythropoiesis In Vitro
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
It has previously been demonstrated that the self-inactivating
gamma-globin lentiviral vector GGHI can significantly increase fetal
hemoglobin (HbF) in erythroid cells from thalassemia patients and thus
improve the disease phenotype in vitro. In the present study, the GGHI
vector was improved further by incorporating novel enhancer elements and
also pseudotyping it with the baboon endogenous virus envelope
glycoprotein BaEVRless, which efficiently and specifically targets human
CD34(+) cells. We evaluated the hypothesis that the newly constructed
vector designated as GGHI-mB-3D would increase hCD34(+) cell tropism and
thus transduction efficiency at low multiplicity of infection, leading
to increased transgene expression. High and stable HbF expression was
demonstrated in thalassemic cells for the resulting GGHI-mB-3D/BaEVRless
vector, exhibiting increased transduction efficiency compared to the
original GGHI-mB-3D/VSVG vector, with a concomitant 91% mean HbF
increase at a mean vector copy number per cell of 0.86 and a mean
transduction efficiency of 56.4%. Transduced populations also exhibited
a trend toward late erythroid, orthochromatic differentiation and
reduced apoptosis, a further indication of successful gene therapy
treatment. Monitoring expression of ATG5, a key link between autophagy
and apoptosis, it was established that this correction correlates with a
reduction of enhanced autophagy activation, a typical feature of
thalassemic polychromatophilic normoblasts. This work provides novel
mechanistic insights into gene therapy-mediated correction of
erythropoiesis and demonstrates the beneficial role of BaEVRless
envelope glycoprotein compared to VSVG pseudotyping and of the novel
GGHI-mB-3D/BaEVRless lentiviral vector for enhanced thalassemia gene
therapy.
Συγγραφείς:
Drakopoulou, Ekati
Georqomanoli, Maria
Lederer, Carsten W. and
Kleanthous, Marina
Costa, Caroline
Bernadin, Ornellie and
Cosset, Francois-Loic
Voskaridou, Ersi
Verhoeyen, Els and
Papanikolaou, Eleni
Anagnou, Nicholas P.
Περιοδικό:
Human Gene Therapy
Εκδότης:
MARY ANN LIEBERT INC PUBL
Λέξεις-κλειδιά:
beta-thalassemia; gene therapy; gamma-globin lentiviral vector; HbF;
BaEVRless; envelope glycoproteins
DOI:
10.1089/hum.2018.022
