Immunomodulatory gene therapy prevents antibody formation and lethal hypersensitivity reactions in murine pompe disease.
Infantile Pompe disease progresses to a lethal cardiomyopathy in absence of effective treatment. Enzyme-replacement therapy (ERT) with recombinant human acid alpha-glucosidase (rhGAA) has been effective in most patients with Pompe disease, but efficacy was reduced by high-titer antibody responses. Immunomodulatory gene therapy with a low dose adeno-associated virus (AAV) vector (2 x 10(10) particles) containing a liver-specific regulatory cassette significantly lowered immunoglobin G (IgG), IgG1, and IgE antibodies to GAA in Pompe disease mice, when compared with mock-treated mice (P < 0.05). AAV-LSPhGAApA had the same effect on GAA-antibody production whether it was given prior to, following, or simultaneously with the initial GAA injection. Mice given AAV-LSPhGAApA had significantly less decrease in body temperature (P < 0.001) and lower anaphylactic scores (P < 0.01) following the GAA challenge. Mouse mast cell protease-1 (MMCP-1) followed the pattern associated with hypersensitivity reactions (P < 0.05). Regulatory T cells (Treg) were demonstrated to play a role in the tolerance induced by gene therapy as depletion of Treg led to an increase in GAA-specific IgG (P < 0.001). Treg depleted mice were challenged with GAA and had significantly stronger allergic reactions than mice given gene therapy without subsequent Treg depletion (temperature: P < 0.01; symptoms: P < 0.05). Ubiquitous GAA expression failed to prevent antibody formation. Thus, immunomodulatory gene therapy could provide adjunctive therapy in lysosomal storage disorders treated by enzyme replacement.
Sun
Baodong
B
Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA.
Kulis
Michael D
MD
Young
Sarah P
SP
Hobeika
Amy C
AC
Li
Songtao
S
Bird
Andrew
A
Zhang
Haoyue
H
Li
Yifan
Y
Clay
Timothy M
TM
Burks
Wesley
W
Kishnani
Priya S
PS
Koeberl
Dwight D
DD
D000818:Animals; D000917:Antibody Formation / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics / Q000502:physiology*; D056947:Enzyme Replacement Therapy / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay; D015316:Genetic Therapy / Q000379:methods*; D006009:Glycogen Storage Disease Type II / Q000276:immunology* / Q000628:therapy*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D000520:alpha-Glucosidases / Q000235:genetics / Q000502:physiology
C509951:GAA protein, human; D000520:alpha-Glucosidases
Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11854-9
12192090
Am J Hum Genet. 2007 Nov;81(5):1042-9
17924344
Neurology. 2007 Jan 9;68(2):99-109
17151339
JAMA. 2001 Jun 6;285(21):2743-9
11386930
Blood. 2008 Aug 1;112(3):610-8
18519811
Mol Genet Metab. 2003 Sep-Oct;80(1-2):159-69
14567965
Blood. 2007 Aug 15;110(4):1132-40
17438084
Lancet. 2003 May 10;361(9369):1608-13
12747881
J Clin Invest. 2008 Aug;118(8):2868-76
18654665
Transplant Proc. 2006 Dec;38(10):3207-8
17175224
Int Arch Allergy Immunol. 2009;148(2):109-17
18802355
Hum Gene Ther. 2008 Jun;19(6):609-21
18500944
Mol Ther. 2004 Feb;9(2):231-40
14759807
Pediatrics. 2004 Oct;114(4):e532-5
15466083
J Biol Chem. 1998 Jul 24;273(30):19086-92
9668092
N Engl J Med. 2001 Jul 5;345(1):9-16
11439963
N Engl J Med. 2009 Jan 8;360(2):194-5
19129538
Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):8861-6
10430861
Pediatrics. 2007 Jul;120(1):e37-46
17606547
Br J Haematol. 2007 Aug;138(3):305-15
17614818
Blood Coagul Fibrinolysis. 1997 Dec;8 Suppl 2:S23-30
9607110
Hum Gene Ther. 2009 Jul;20(7):767-76
19309290
J Immunol. 2006 Jan 15;176(2):899-904
16393974
Mol Ther. 2005 Nov;12(5):876-84
16005263
Genet Med. 2009 Mar;11(3):210-9
19287243
J Allergy Clin Immunol. 2003 Jul;112(1):159-67
12847493
Mol Ther. 2005 Jan;11(1):57-65
15585406
Mol Ther. 2003 Apr;7(4):467-77
12727109
Mol Ther. 2006 Dec;14(6):822-30
16987711
Clin Exp Allergy. 2007 Apr;37(4):572-81
17430355
Immunol Rev. 2005 Aug;206:232-59
16048553
Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3906-10
10097136
Blood. 2004 Feb 15;103(4):1253-60
14551134
Scand J Gastroenterol. 2006 Dec;41(12):1405-13
17101571
Genet Med. 2001 Mar-Apr;3(2):132-8
11286229
Pediatrics. 2004 May;113(5):e448-57
15121988
Blood. 2006 Jul 15;108(2):480-6
16543469
Curr Gene Ther. 2007 Oct;7(5):381-90
17979684
Mol Genet Metab. 2008 Jul;94(3):313-8
18456533
Mol Ther. 2000 Feb;1(2):154-8
10933925
J Pediatr. 2006 Jul;149(1):89-97
16860134