Plerixafor+G-CSF–mobilized CD34+ cells represent an optimal graft source for thalassemia gene therapy

Karponi, Garyfalia; Psatha, Nikoletta; Lederer, Carsten W.; Adair, Jennifer E.; Zervou, Fani; Zogas, Nikolaos; Kleanthous, Marina; Tsatalas, Constantinos; Anagnostopoulos, Achilles; Sadelain, Michel; Rivière, Isabelle; Stamatoyannopoulos, George; Yannaki, Evangelia

doi:10.1182/blood-2015-03-629618

Cited by 44 publications

(49 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…170 Plerixafor is an alternative mobilizing agent that may provide a safer option to G-CSF. 170,172,173 Although the effect of plerixafor in SCD patients requires investigation, it has been shown to be safe and effective in both splenectomized and nonsplenectomized b-thalassemia patients. In contrast, although G-CSF was well tolerated in nonsplenectomized patients, it resulted in hyperleukocytosis and lower yield of CD34…”

Section: Steps To Clinical Translationmentioning

confidence: 99%

See 1 more Smart Citation

Customizing the genome as therapy for the β-hemoglobinopathies

Canver

Orkin

2016

Blood

View full text Add to dashboard Cite

Despite nearly complete understanding of the genetics of the β-hemoglobinopathies for several decades, definitive treatment options have lagged behind. Recent developments in technologies for facile manipulation of the genome (zinc finger nucleases, transcription activator-like effector nucleases, or clustered regularly interspaced short palindromic repeats–based nucleases) raise prospects for their clinical application. The use of genome-editing technologies in autologous CD34+ hematopoietic stem and progenitor cells represents a promising therapeutic avenue for the β-globin disorders. Genetic correction strategies relying on the homology-directed repair pathway may repair genetic defects, whereas genetic disruption strategies relying on the nonhomologous end joining pathway may induce compensatory fetal hemoglobin expression. Harnessing the power of genome editing may usher in a second-generation form of gene therapy for the β-globin disorders.

show abstract

Section: Steps To Clinical Translationmentioning

confidence: 99%

“…172 Combination of plerixafor with a reduced dose of G-CSF to avoid adverse effects has been shown to be superior to either agent alone. 170,173 Therefore, plerixafor or combination G-CSF/plerixafor mobilization may provide a safe avenue for peripheral blood CD34 …”

mentioning

confidence: 99%

Customizing the genome as therapy for the β-hemoglobinopathies

Canver

Orkin

2016

Blood

View full text Add to dashboard Cite

show abstract

“…Extensive studies from our group using thalassemia as a model, have defined Plerixafor+G-CSF-mobilized cells as an optimal graft source for thalassemia GT but also for HSC-GT applications in general; they do not only contain very high numbers of CD34+ cells obtained through single collections [46], but importantly also, demonstrate superior competitive long-term engraftment in a thalassemic mouse model [47] or enhanced early human chimerism after transduction/transplantation under a non-myeloablative conditioning, in xenografts[48]. Despite in fact, that transduction rates with a lentiviral globin vector were lower for Plerixafor+G-CSF-cells compared to cells mobilized with either agent alone, there was increased β-globin expression per vector copy, implying that a given required level of expression might be achieved at a lower vector copy number, thus providing higher biosafety in GT applications.…”

Section: Enrichment Of Human Stem/progenitor Cells In Gene-engineeredmentioning

confidence: 99%

Optimizing autologous cell grafts to improve stem cell gene therapy

Psatha

Karponi

Yannaki

2016

Experimental Hematology

Self Cite

View full text Add to dashboard Cite

Over the past decade, stem cell gene therapy has achieved unprecedented curative outcomes for several genetic disorders. Despite the unequivocal success, clinical gene therapy still faces challenges. Genetically-engineered hematopoietic stem cells (HSCs) are particularly vulnerable to attenuation of their repopulating capacity once exposed to culture conditions, ultimately leading to low engraftment levels post-transplant. This becomes of particular importance when transduction rates are low or/and competitive transplant conditions are generated by a reduced intensity conditioning in the absence of a selective advantage of the transduced over the unmodified cells. These limitations could partially be overcome by introducing mega-doses of genetically-modified CD34+cells into conditioned patients or by transplanting HSCs with high engrafting and repopulating potential. In the present review, based on the lessons gained from the cord blood transplantation, we summarize the most promising approaches to date of increasing either the numbers of HSCs for transplantation or/and their engraftability, as a platform towards the optimization of engineered stem cell grafts.

show abstract

“…10 Many different approaches were investigated to improve the efficiency of transduction and engraftment with the goal of increasing the number of genetically modified cells in peripheral blood. [11][12][13][14][15][16] One such approach is to express a HOX protein that confers a benign proliferative advantage to the modified cells over the non-transduced cells in vivo. 15,17,18 HOXB4 was the first HOX family member found to enhance the expansion of human and mouse HSCs by promoting self-renewal divisions without losing stemness.…”

Section: Introductionmentioning

confidence: 99%