Rapamycin relieves lentiviral vector transduction resistance in human and mouse hematopoietic stem cells

Wang, Cathy X.; Sather, Blythe; Wang, Xuefeng; Adair, Jennifer E.; Khan, Iram; Singh, Swati; Lang, Shanshan; Adams, Amie B.; Curinga, Gabrielle; Kiem, Hans Peter; Miao, Carol H.; Rawlings, David J.; Torbett, Bruce E.

doi:10.1182/blood-2013-12-546218

Cited by 75 publications

(80 citation statements)

References 57 publications

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“…However, the addition of rapamycin during VSV-G-LV transduction of resting hCD34 1 cells did not significantly increase transduction. 61,62 This is in accordance with the absence of the VSV receptor low-density lipoprotein on resting hCD34…”

Section: Discussionsupporting

confidence: 81%

“…However, caution is warranted because of the known cell cycle blockage this drug induces. 61 We identified CD46 as the MV receptor that allows this spectacular H/F-LV transduction efficiency for as well as quiescent as cytokine-stimulated HSCs. This is reinforced by the fact that retronectin increased H/F-LV transduction of resting CD34…”

Section: Discussionmentioning

confidence: 94%

“…This means that the H/F-LVs overcome an important barrier for clinical gene therapy using VSV-G-LVs, which demonstrate limited efficiency in particular in resting HSCs. 12,35,60,61 It is essential to transduce HSCs without changing their capacity for self-renewal, homing, and differentiation, which is supported by minimal or no stimulation of these targets. Moreover, cytokine stimulation induces HSCs to exit their quiescent state accompanied by induction of DNA damage in these cells.…”

Section: Discussionmentioning

confidence: 99%

“…Wang and colleagues 61 showed that rapamycin strongly facilitated efficient VSV-G-LV transduction in prestimulated hCD34…”

Section: Discussionmentioning

confidence: 99%

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Measles virus envelope pseudotyped lentiviral vectors transduce quiescent human HSCs at an efficiency without precedent

et al. 2017

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

“…Wang and colleagues 61 showed that rapamycin strongly facilitated efficient VSV-G-LV transduction in prestimulated hCD34…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Measles virus envelope pseudotyped lentiviral vectors transduce quiescent human HSCs at an efficiency without precedent

et al. 2017

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“…Most of these methods, however, result in only incremental effects on overall transduction efficiency, are not scalable (centrifugation), are highly dependent on vector quality (infectious titer), and are subject to patient-specific variability. Recently, however, Wang and Torbett [14] reported that rapamycin enhanced lentiviral transduction of cord blood and bone marrowderived HSPCs from several species. Rapamycin (sirolimus) is a nonantibiotic macrolide with pleiotropic activity, including immunosuppression and regulation of cell cycling and autophagy [15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Enhanced Genetic Modification of Adult Growth Factor Mobilized Peripheral Blood Hematopoietic Stem and Progenitor Cells With Rapamycin

Torres-Coronado

et al. 2014

Stem Cells Translational Medicine

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Genetic modification of adult human hematopoietic stem and progenitor cells (HSPCs) with lentiviral vectors leads to long‐term gene expression in the progeny of the HSPCs and has been used to successfully treat several monogenic diseases. In some cases, the gene‐modified cells have a selective growth advantage over nonmodified cells and eventually are the dominant engrafted population. However, in disease indications for which the gene‐modified cells do not have a selective advantage, optimizing transduction of HSPC is paramount to successful stem cell‐based gene therapy. We demonstrate here that transduction of adult CD34+ HSPCs with lentiviral vectors in the presence of rapamycin, a widely used mTORC1 inhibitor, results in an approximately threefold increase in stable gene marking with minimal effects on HSPC growth and differentiation. Using this approach, we have demonstrated that we can enhance the frequency of gene‐modified HSPCs that give rise to clonogenic progeny in vitro without excessive increases in the number of vector copies per cell or changes in integration pattern. The genetic marking of HSPCs and expression of transgenes is durable, and transplantation of gene‐modified HSPCs into immunodeficient mice results in high levels of gene marking of the lymphoid and myeloid progeny in vivo. The prior safe clinical history of rapamycin in other applications supports the use of this compound to generate gene‐modified autologous HSPCs for our HIV gene therapy clinical trials.

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Adenovirus vectors in hematopoietic stem cell genome editing

Lieber

2019

FEBS Letters

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Genome editing of hematopoietic stem cells (HSCs) represents a therapeutic option for a number of hematological genetic diseases, as HSCs have the potential for self-renewal and differentiation into all blood cell lineages. This review presents advances of genome editing in HSCs utilizing adenovirus vectors as delivery vehicles. We focus on capsid-modified, helper-dependent adenovirus vectors that are devoid of all viral genes and therefore exhibit an improved safety profile. We discuss HSC genome engineering for several inherited disorders and infectious diseases including hemoglobinopathies, Fanconi anemia, hemophilia, and HIV-1 infection by ex vivo and in vivo editing in transgenic mice, nonhuman primates, as well as in human CD34 + cells. Mechanisms of therapeutic gene transfer including episomal expression of designer nucleases and base editors, transposase-mediated random integration, and targeted homology-directed repair triggered integration into selected genomic safe harbor loci are also reviewed.

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Rapamycin relieves lentiviral vector transduction resistance in human and mouse hematopoietic stem cells

Abstract: Key Points Rapamycin significantly enhances lentiviral vector gene delivery to hematopoietic stem cells while preserving engraftment potential. Rapamycin-mediated transduction enhancement is not accompanied by alterations in lentiviral integration profile.

Cited by 75 publications

References 57 publications

Measles virus envelope pseudotyped lentiviral vectors transduce quiescent human HSCs at an efficiency without precedent

Measles virus envelope pseudotyped lentiviral vectors transduce quiescent human HSCs at an efficiency without precedent

Enhanced Genetic Modification of Adult Growth Factor Mobilized Peripheral Blood Hematopoietic Stem and Progenitor Cells With Rapamycin

Adenovirus vectors in hematopoietic stem cell genome editing

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