Improved Titer and Gene Transfer by Lentiviral Vectors Using Novel, Small β-Globin Locus Control Region Elements.
Anemia, Sickle Cell
/ therapy
Animals
Bone Marrow Cells
/ metabolism
Disease Models, Animal
Genetic Therapy
/ methods
Genetic Vectors
HEK293 Cells
Healthy Volunteers
Hematopoietic Stem Cells
/ metabolism
Humans
Lentivirus
/ genetics
Locus Control Region
/ genetics
Mice
Phenotype
Transduction, Genetic
/ methods
Transfection
beta-Globins
/ genetics
ENCODE
gene therapy
hematopoietic stem cell
hemoglobinopathies
lentiviral vector
locus control region
sickle cell disease
transplantation
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
08 01 2020
08 01 2020
Historique:
received:
27
05
2019
revised:
11
09
2019
accepted:
19
09
2019
pubmed:
20
10
2019
medline:
22
12
2020
entrez:
20
10
2019
Statut:
ppublish
Résumé
β-globin lentiviral vectors (β-LV) have faced challenges in clinical translation for gene therapy of sickle cell disease (SCD) due to low titer and sub-optimal gene transfer to hematopoietic stem and progenitor cells (HSPCs). To overcome the challenge of preserving efficacious expression while increasing vector performance, we used published genomic and epigenomic data available through ENCODE to redefine enhancer element boundaries of the β-globin locus control region (LCR) to construct novel ENCODE core sequences. These novel LCR elements were used to design a β-LV of reduced proviral length, termed CoreGA-AS3-FB, produced at higher titers and possessing superior gene transfer to HSPCs when compared to the full-length parental β-LV at equal MOI. At low vector copy number, vectors containing the ENCODE core sequences were capable of reversing the sickle phenotype in a mouse model of SCD. These studies provide a β-LV that will be beneficial for gene therapy of SCD by significantly reducing the cost of vector production and extending the vector supply.
Identifiants
pubmed: 31628051
pii: S1525-0016(19)30449-6
doi: 10.1016/j.ymthe.2019.09.020
pmc: PMC6953778
pii:
doi:
Substances chimiques
beta-Globins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
328-340Subventions
Organisme : NHLBI NIH HHS
ID : F31 HL134313
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008042
Pays : United States
Organisme : NIGMS NIH HHS
ID : T34 GM008563
Pays : United States
Informations de copyright
Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.
Références
Mol Ther Methods Clin Dev. 2015 Apr 22;2:15012
pubmed: 26029723
Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6605-9
pubmed: 8692864
Am J Hematol. 2019 May;94(5):522-527
pubmed: 30680775
Hum Gene Ther Methods. 2018 Apr;29(2):104-113
pubmed: 29631437
Nature. 2012 Sep 6;489(7414):57-74
pubmed: 22955616
Nature. 2010 Sep 16;467(7313):318-22
pubmed: 20844535
Blood. 2011 Jul 7;118(1):19-27
pubmed: 21490337
Biochim Biophys Acta. 1963 Dec 13;78:637-43
pubmed: 14092068
Curr Gene Ther. 2015;15(1):64-81
pubmed: 25429463
Blood. 2009 Aug 6;114(6):1174-85
pubmed: 19474450
Cell Stem Cell. 2018 Dec 6;23(6):820-832.e9
pubmed: 30416070
Blood. 2007 Dec 15;110(13):4175-8
pubmed: 17921347
Cell. 1987 Dec 24;51(6):975-85
pubmed: 3690667
Nucleic Acids Res. 2012 Dec;40(22):11256-69
pubmed: 23042246
Blood. 2003 Dec 15;102(13):4312-9
pubmed: 12933581
J Virol. 1998 Nov;72(11):8463-71
pubmed: 9765382
Genes Dev. 1993 Jan;7(1):106-13
pubmed: 8422981
N Engl J Med. 2018 Apr 19;378(16):1479-1493
pubmed: 29669226
J Clin Invest. 2013 Jul 1;:null
pubmed: 23863630
Blood Cells Mol Dis. 2007 Jul-Aug;39(1):44-55
pubmed: 17433733
Science. 1997 Oct 31;278(5339):873-6
pubmed: 9346487
Br J Haematol. 1978 Nov;40(3):415-29
pubmed: 749927
J Biol Chem. 2004 Jun 25;279(26):27518-24
pubmed: 15084588
Pediatr Blood Cancer. 2015 Jul;62(7):1285-7
pubmed: 25663074
EMBO J. 1990 Jan;9(1):233-40
pubmed: 2295312
Cytotherapy. 2017 Sep;19(9):1096-1112
pubmed: 28733131
N Engl J Med. 1994 Jun 9;330(23):1639-44
pubmed: 7993409
N Engl J Med. 2017 Mar 2;376(9):848-855
pubmed: 28249145
Blood. 1991 Apr 1;77(7):1405-14
pubmed: 2009364
N Engl J Med. 2018 Jul 19;379(3):226-235
pubmed: 30021096
Mol Cell Biol. 2003 Dec;23(24):8946-52
pubmed: 14645507
J Virol Methods. 2011 Oct;177(1):1-9
pubmed: 21784103
Hum Gene Ther. 2001 Oct 10;12(15):1893-905
pubmed: 11589831
Proc Natl Acad Sci U S A. 1989 Jul;86(14):5439-43
pubmed: 2748594
Nature. 2000 Jul 6;406(6791):82-6
pubmed: 10894546
Mol Ther Methods Clin Dev. 2018 Aug 08;10:341-347
pubmed: 30191160
Ann N Y Acad Sci. 1998 Jun 30;850:38-44
pubmed: 9668525
BMC Res Notes. 2016 Jun 16;9:312
pubmed: 27306375
Hum Gene Ther. 2018 Oct;29(10):1153-1166
pubmed: 30198339
N Engl J Med. 1995 May 18;332(20):1317-22
pubmed: 7715639
Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10547-52
pubmed: 18650378
Blood. 2002 Mar 15;99(6):1902-8
pubmed: 11877258
Science. 2001 Dec 14;294(5550):2368-71
pubmed: 11743206
Nature. 1957 Aug 17;180(4581):326-8
pubmed: 13464827
Genes Dev. 1989 Mar;3(3):314-23
pubmed: 2721958
J Mol Biol. 2001 Sep 7;312(1):17-26
pubmed: 11545582
Anal Chem. 2011 Nov 15;83(22):8604-10
pubmed: 22035192
Nucleic Acids Res. 1990 Jun 25;18(12):3503-8
pubmed: 2362805