Abstract:
:Therapeutic gene delivery to hematopoietic stem cells (HSCs) holds great potential as a life-saving treatment of monogenic, oncologic, and infectious diseases. However, clinical gene therapy is severely limited by intrinsic HSC resistance to modification with lentiviral vectors (LVs), thus requiring high doses or repeat LV administration to achieve therapeutic gene correction. Here we show that temporary coapplication of the cyclic resveratrol trimer caraphenol A enhances LV gene delivery efficiency to human and nonhuman primate hematopoietic stem and progenitor cells with integrating and nonintegrating LVs. Although significant ex vivo, this effect was most dramatically observed in human lineages derived from HSCs transplanted into immunodeficient mice. We further show that caraphenol A relieves restriction of LV transduction by altering the levels of interferon-induced transmembrane (IFITM) proteins IFITM2 and IFITM3 and their association with late endosomes, thus augmenting LV core endosomal escape. Caraphenol A-mediated IFITM downregulation did not alter the LV integration pattern or bias lineage differentiation. Taken together, these findings compellingly demonstrate that the pharmacologic modification of intrinsic immune restriction factors is a promising and nontoxic approach for improving LV-mediated gene therapy.
journal_name
Bloodjournal_title
Bloodauthors
Ozog S,Timberlake ND,Hermann K,Garijo O,Haworth KG,Shi G,Glinkerman CM,Schefter LE,D'Souza S,Simpson E,Sghia-Hughes G,Carillo RR,Boger DL,Kiem HP,Slukvin I,Ryu BY,Sorrentino BP,Adair JE,Snyder SA,Compton AA,Torbetdoi
10.1182/blood.2019000040subject
Has Abstractpub_date
2019-10-17 00:00:00pages
1298-1311issue
16eissn
0006-4971issn
1528-0020pii
blood.2019000040journal_volume
134pub_type
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