Lentiviral Hematopoietic Stem Cell Gene Therapy Rescues Clinical Phenotypes in a Murine Model of Pompe Disease.
GAA
Pompe disease
acid alpha-glucosidase
erythroid-specific enhancer
hematopoietic stem cell gene therapy
lentiviral vector
lysosomal storage disorders
personalized medicine
Journal
Molecular therapy. Methods & clinical development
ISSN: 2329-0501
Titre abrégé: Mol Ther Methods Clin Dev
Pays: United States
ID NLM: 101624857
Informations de publication
Date de publication:
11 Sep 2020
11 Sep 2020
Historique:
received:
07
03
2020
accepted:
02
07
2020
entrez:
11
8
2020
pubmed:
11
8
2020
medline:
11
8
2020
Statut:
epublish
Résumé
Pompe disease is a lysosomal storage disorder caused by malfunctions of the acid alpha-glucosidase (GAA) enzyme with a consequent toxic accumulation of glycogen in cells. Muscle wasting and hypertrophic cardiomyopathy are the most common clinical signs that can lead to cardiac and respiratory failure within the first year of age in the more severe infantile forms. Currently available treatments have significant limitations and are not curative, highlighting a need for the development of alternative therapies. In this study, we investigated the use of a clinically relevant lentiviral vector to deliver systemically GAA through genetic modification of hematopoietic stem and progenitor cells (HSPCs). The overexpression of GAA in human HSPCs did not exert any toxic effect on this cell population, which conserved its stem cell capacity in xenograft experiments. In a murine model of Pompe disease treated at young age, we observed phenotypic correction of heart and muscle function with a significant reduction of glycogen accumulation in tissues after 6 months of treatment. These findings suggest that lentiviral-mediated HSPC gene therapy can be a safe alternative therapy for Pompe disease.
Identifiants
pubmed: 32775491
doi: 10.1016/j.omtm.2020.07.001
pii: S2329-0501(20)30150-9
pmc: PMC7396971
doi:
Types de publication
Journal Article
Langues
eng
Pagination
558-570Subventions
Organisme : British Heart Foundation
ID : FS/15/33/31608
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R026416/1
Pays : United Kingdom
Informations de copyright
© 2020 The Authors.
Références
Mol Ther Methods Clin Dev. 2014 Jun 11;1:14018
pubmed: 26015962
Ann Transl Med. 2019 Jul;7(13):288
pubmed: 31392200
Mol Ther. 2012 May;20(5):1014-21
pubmed: 22434137
PLoS One. 2011;6(9):e24826
pubmed: 21935475
Mol Ther Methods Clin Dev. 2019 Apr 06;13:399-413
pubmed: 31044143
Biochem J. 2005 Aug 1;389(Pt 3):619-28
pubmed: 15839836
N Engl J Med. 2011 Dec 22;365(25):2357-65
pubmed: 22149959
Genet Med. 2020 May;22(5):898-907
pubmed: 31904026
Pediatr Pulmonol. 2020 Mar;55(3):674-681
pubmed: 31899940
Mol Ther. 2007 Sep;15(9):1630-9
pubmed: 17609656
J Neuromuscul Dis. 2020;7(1):15-31
pubmed: 31796685
J Clin Invest. 2006 Nov;116(11):3070-82
pubmed: 17080200
Hum Gene Ther. 2013 Jun;24(6):630-40
pubmed: 23570273
Neurology. 2008 Dec 2;71(23 Suppl 2):S12-36
pubmed: 19047571
J Inherit Metab Dis. 2012 Mar;35(2):311-6
pubmed: 21687968
EMBO Mol Med. 2018 Jul;10(7):
pubmed: 29884617
Hum Gene Ther. 2016 Oct;27(10):813-829
pubmed: 27431943
Mol Genet Metab. 2010 Jan;99(1):26-33
pubmed: 19775921
Hum Gene Ther. 2005 Jan;16(1):68-80
pubmed: 15703490
Pediatr Neonatol. 2013 Aug;54(4):219-27
pubmed: 23632029
Blood. 2010 Jul 1;115(26):5329-37
pubmed: 20385789
J Biol Chem. 2013 Jan 18;288(3):1428-38
pubmed: 23188827
PLoS One. 2010 Aug 26;5(8):e12413
pubmed: 20865032
Mol Ther. 2012 Jul;20(7):1400-9
pubmed: 22434141
J Biol Chem. 2005 Feb 25;280(8):6780-91
pubmed: 15520017
Mol Ther. 2006 Oct;14(4):505-13
pubmed: 16905365
Science. 2009 Nov 6;326(5954):818-23
pubmed: 19892975
Mol Ther Methods Clin Dev. 2019 Jun 07;14:134-147
pubmed: 31338385
Front Pediatr. 2019 Oct 31;7:443
pubmed: 31737588
Science. 2013 Aug 23;341(6148):1233158
pubmed: 23845948
J Clin Invest. 2004 Apr;113(8):1118-29
pubmed: 15085191
Neurology. 2005 Jun 28;64(12):2139-41
pubmed: 15985590
Mol Ther Methods Clin Dev. 2018 Nov 17;12:85-101
pubmed: 30581888
JCI Insight. 2019 Mar 7;4(5):
pubmed: 30843882
Mol Ther. 2015 Apr;23(4):737-45
pubmed: 25523759
Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2680-5
pubmed: 24550296
Sci Transl Med. 2010 Nov 17;2(58):58ra84
pubmed: 21084719
IUBMB Life. 2011 Nov;63(11):979-86
pubmed: 22002928
Front Aging Neurosci. 2014 Jul 23;6:177
pubmed: 25183957
Nat Commun. 2017 Oct 24;8(1):1111
pubmed: 29061980
Mol Ther. 2013 Oct;21(10):1938-49
pubmed: 23748415
Blood. 2010 Dec 9;116(24):5130-9
pubmed: 20847202
BMC Res Notes. 2016 Jun 16;9:312
pubmed: 27306375
Neurology. 2019 Nov 5;93(19):e1756-e1767
pubmed: 31619483
Ann Transl Med. 2019 Jul;7(13):289
pubmed: 31392201
Int J Pharm. 2015 Aug 1;491(1-2):69-77
pubmed: 26056928
Front Immunol. 2014 Jul 23;5:350
pubmed: 25101090
Cell Stem Cell. 2017 Nov 2;21(5):574-590
pubmed: 29100011
Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9419-24
pubmed: 19474295
Gene Ther. 2017 May;24(5):298-307
pubmed: 28346436
Mol Ther. 2015 May;23(5):835-844
pubmed: 25655314
Mol Ther Methods Clin Dev. 2020 May 04;17:1014-1025
pubmed: 32462050
Blood. 2000 Nov 15;96(10):3392-8
pubmed: 11071633
Nat Biotechnol. 2005 Jan;23(1):69-74
pubmed: 15619619
Stem Cells Dev. 2008 Apr;17(2):279-89
pubmed: 18447643
Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):19958-63
pubmed: 19903883
Ann Transl Med. 2019 Jul;7(13):287
pubmed: 31392199
J Gene Med. 2009 Apr;11(4):279-87
pubmed: 19263466
Sci Transl Med. 2017 Nov 29;9(418):
pubmed: 29187643
N Engl J Med. 2017 Oct 26;377(17):1630-1638
pubmed: 28976817
Mol Ther. 2009 Jun;17(6):954-63
pubmed: 19277015
Hum Gene Ther. 2015 Jun;26(6):357-66
pubmed: 25761450
J Mol Med (Berl). 2017 May;95(5):513-521
pubmed: 28154884
Neurology. 2008 Dec 2;71(23 Suppl 2):S4-11
pubmed: 19047572
Pediatr Endocrinol Rev. 2014 Sep;12 Suppl 1:114-24
pubmed: 25345093
Lancet. 2016 Jul 30;388(10043):476-87
pubmed: 27289174
Hum Mol Genet. 2011 Apr 15;20(R1):R42-53
pubmed: 21459776