AAV-mediated delivery of an anti-BACE1 VHH alleviates pathology in an Alzheimer's disease model.
Alzheimer Disease
/ pathology
Amyloid Precursor Protein Secretases
/ immunology
Amyloid beta-Peptides
/ metabolism
Animals
Aspartic Acid Endopeptidases
/ immunology
Blood-Brain Barrier
Dependovirus
/ genetics
Disease Models, Animal
Genetic Vectors
/ therapeutic use
Mice
Mice, Transgenic
Single-Domain Antibodies
AAV
Alzheimer’s disease
VHH
anti-BACE1
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
07 04 2022
07 04 2022
Historique:
revised:
11
02
2022
received:
15
07
2019
accepted:
14
02
2022
pubmed:
31
3
2022
medline:
9
4
2022
entrez:
30
3
2022
Statut:
ppublish
Résumé
Single domain antibodies (VHHs) are potentially disruptive therapeutics, with important biological value for treatment of several diseases, including neurological disorders. However, VHHs have not been widely used in the central nervous system (CNS), largely because of their restricted blood-brain barrier (BBB) penetration. Here, we propose a gene transfer strategy based on BBB-crossing adeno-associated virus (AAV)-based vectors to deliver VHH directly into the CNS. As a proof-of-concept, we explored the potential of AAV-delivered VHH to inhibit BACE1, a well-characterized target in Alzheimer's disease. First, we generated a panel of VHHs targeting BACE1, one of which, VHH-B9, shows high selectivity for BACE1 and efficacy in lowering BACE1 activity in vitro. We further demonstrate that a single systemic dose of AAV-VHH-B9 produces positive long-term (12 months plus) effects on amyloid load, neuroinflammation, synaptic function, and cognitive performance, in the App
Identifiants
pubmed: 35352880
doi: 10.15252/emmm.201809824
pmc: PMC8988209
doi:
Substances chimiques
Amyloid beta-Peptides
0
Single-Domain Antibodies
0
Amyloid Precursor Protein Secretases
EC 3.4.-
Aspartic Acid Endopeptidases
EC 3.4.23.-
Bace1 protein, mouse
EC 3.4.23.46
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e09824Informations de copyright
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.
Références
Genes Brain Behav. 2004 Oct;3(5):303-14
pubmed: 15344923
Biochimie. 2015 Apr;111:82-106
pubmed: 25656912
Front Immunol. 2017 Nov 22;8:1603
pubmed: 29213270
Neurol Sci. 2015 Mar;36(3):429-34
pubmed: 25294428
Front Neural Circuits. 2017 Jun 13;11:41
pubmed: 28659766
Neurobiol Aging. 2013 Jul;34(7):1779-89
pubmed: 23474291
Mol Neurodegener. 2011 Dec 28;6:88
pubmed: 22204380
Nat Rev Drug Discov. 2018 Sep;17(9):641-659
pubmed: 30093643
J Control Release. 2016 Dec 10;243:1-10
pubmed: 27671875
Alzheimers Res Ther. 2020 Aug 24;12(1):100
pubmed: 32838792
J Alzheimers Dis. 2013;37(4):823-34
pubmed: 23948917
Methods Mol Biol. 2012;907:145-76
pubmed: 22907350
Am J Med Sci. 2002 Jul;324(1):14-30
pubmed: 12120821
Behav Brain Res. 2018 Jan 15;336:177-181
pubmed: 28887197
Am J Physiol Cell Physiol. 2021 Feb 1;320(2):C195-C215
pubmed: 33264078
N Engl J Med. 2019 Jan 24;380(4):335-346
pubmed: 30625070
Front Immunol. 2021 Mar 09;12:632687
pubmed: 33767701
J Nucl Med. 2008 May;49(5):788-95
pubmed: 18413403
J Biol Chem. 2014 Nov 7;289(45):30977-89
pubmed: 25253695
J Biomed Sci. 2020 Jan 2;27(1):1
pubmed: 31894001
EMBO Mol Med. 2012 Sep;4(9):980-91
pubmed: 22903875
Life Sci Alliance. 2018 Feb 15;1(1):e201800026
pubmed: 30456346
J Biol Chem. 2011 Mar 11;286(10):8677-8687
pubmed: 21209097
Science. 1999 Oct 22;286(5440):735-41
pubmed: 10531052
J Cell Biol. 1999 Oct 18;147(2):277-94
pubmed: 10525535
Clin Dev Immunol. 2012;2012:980250
pubmed: 22474489
FEBS J. 2015 Sep;282(18):3618-31
pubmed: 26147692
Sci Rep. 2012;2:231
pubmed: 22355745
J Neurosci. 2021 Mar 17;41(11):2475-2495
pubmed: 33472828
Hum Gene Ther Methods. 2013 Apr;24(2):59-67
pubmed: 23442094
Expert Opin Biol Ther. 2014 Oct;14(10):1465-76
pubmed: 24981190
Hum Mol Genet. 2017 Apr 1;26(7):1353-1364
pubmed: 28334940
J Biol Chem. 2007 Sep 7;282(36):26326-34
pubmed: 17616527
Biol Psychiatry. 2018 Mar 1;83(5):428-437
pubmed: 28129943
Nature. 2012 Aug 2;488(7409):96-9
pubmed: 22801501
Fluids Barriers CNS. 2018 Mar 20;15(1):10
pubmed: 29558954
Brain Res Bull. 2011 Jul 15;85(6):354-62
pubmed: 21501666
Trends Neurosci. 2016 Mar;39(3):158-169
pubmed: 26833257
J Biol Chem. 2014 Nov 7;289(45):30990-1000
pubmed: 25253696
Anal Biochem. 1977 Dec;83(2):346-56
pubmed: 603028
Curr Gene Ther. 2017;16(6):363-374
pubmed: 28042779
Proc Natl Acad Sci U S A. 2004 Oct 5;101(40):14515-20
pubmed: 15452348
Mol Neurodegener. 2016 Oct 5;11(1):67
pubmed: 27716410
Nat Commun. 2017 May 05;8:15178
pubmed: 28474669
J Neurosci. 2017 Mar 8;37(10):2639-2655
pubmed: 28159908
Nat Rev Neurol. 2021 Nov;17(11):703-714
pubmed: 34548654
N Engl J Med. 2019 Apr 11;380(15):1483-1485
pubmed: 30970197
Cell Rep. 2020 Jul 14;32(2):107899
pubmed: 32668253
Sci Rep. 2018 Dec 4;8(1):17611
pubmed: 30514850
J Biol Chem. 2016 Feb 19;291(8):3767-75
pubmed: 26677230
Protein Expr Purif. 2002 Oct;26(1):139-48
pubmed: 12356481
Immunol Rev. 2017 Jan;275(1):324-333
pubmed: 28133808
Sci Transl Med. 2011 May 25;3(84):84ra43
pubmed: 21613622
N Engl J Med. 2017 Nov 2;377(18):1713-1722
pubmed: 29091557
Front Psychol. 2015 Nov 26;6:1805
pubmed: 26635701
Neuropharmacology. 2017 Jul 1;120:38-55
pubmed: 26972827
J Control Release. 2018 Dec 10;291:80-89
pubmed: 30342077
J Control Release. 2015 Jan 10;197:78-86
pubmed: 25449807
J Cell Biol. 2004 Sep 27;166(7):1041-54
pubmed: 15452145
Nat Rev Genet. 2020 Apr;21(4):255-272
pubmed: 32042148
J Biol Chem. 2009 Jan 30;284(5):3273-3284
pubmed: 19010777
Behav Brain Res. 2019 May 17;364:431-441
pubmed: 29158112
Nanomedicine (Lond). 2013 Jun;8(6):1013-26
pubmed: 23730699
Nat Struct Mol Biol. 2011 Dec 11;19(1):117-21
pubmed: 22157958
J Neurochem. 2018 Jun;145(5):393-408
pubmed: 29527688
BioDrugs. 2020 Feb;34(1):11-26
pubmed: 31686399
Cell Rep. 2016 Mar 8;14(9):2127-2141
pubmed: 26923602
Sci Transl Med. 2018 Sep 19;10(459):
pubmed: 30232227
Ann Clin Lab Sci. 2005 Summer;35(3):227-9
pubmed: 16081577
Methods. 2004 Oct;34(2):184-99
pubmed: 15312672
Mol Ther. 2020 Mar 4;28(3):723-746
pubmed: 31972133
Mol Ther. 2010 Jan;18(1):80-6
pubmed: 19904234
FASEB J. 2006 Dec;20(14):2576-8
pubmed: 17068112
Cell Tissue Res. 2020 Oct;382(1):65-70
pubmed: 32830288
Nat Biotechnol. 2016 Feb;34(2):204-9
pubmed: 26829320
Front Immunol. 2020 Mar 17;11:449
pubmed: 32256496
Neuron. 2001 Nov 20;32(4):579-89
pubmed: 11719200
Mol Ther. 2021 Feb 3;29(2):859-872
pubmed: 33128896
Nat Neurosci. 2001 Mar;4(3):233-4
pubmed: 11224536
Mol Ther Nucleic Acids. 2015 Nov 17;4:e264
pubmed: 26575098
Biomolecules. 2020 Dec 12;10(12):
pubmed: 33322697
Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):E559-68
pubmed: 21825135
EMBO J. 2017 Sep 1;36(17):2473-2487
pubmed: 28768718
Pharmaceuticals (Basel). 2021 Jun 03;14(6):
pubmed: 34205013
Neuron. 2019 Mar 6;101(5):839-862
pubmed: 30844402
J Vis Exp. 2015 Apr 06;(98):e52462
pubmed: 25867711
Antibodies (Basel). 2019 Apr 05;8(2):
pubmed: 31544833
Drug Discov Today. 2016 Jul;21(7):1076-113
pubmed: 27080147
Hum Gene Ther Clin Dev. 2017 Jun;28(2):74-79
pubmed: 28279081
EMBO Mol Med. 2022 Apr 7;14(4):e09824
pubmed: 35352880
EMBO J. 1998 Jul 1;17(13):3512-20
pubmed: 9649422
Mol Neurodegener. 2012 Aug 14;7:39
pubmed: 22892055
J Neurosci. 2007 Oct 3;27(40):10849-59
pubmed: 17913918
Front Immunol. 2017 Jul 31;8:867
pubmed: 28824615
Mol Ther. 2018 Mar 7;26(3):664-668
pubmed: 29428298
N Engl J Med. 2019 Apr 11;380(15):1476-1478
pubmed: 30970194
Hum Gene Ther. 2016 Jul;27(7):522-7
pubmed: 26711317
Nat Neurosci. 2014 May;17(5):661-3
pubmed: 24728269
Front Plant Sci. 2018 Feb 09;9:130
pubmed: 29479361
EMBO Mol Med. 2014 Feb;6(2):194-211
pubmed: 24150896
N Engl J Med. 2019 Apr 11;380(15):1408-1420
pubmed: 30970186
Curr Opin Struct Biol. 2011 Aug;21(4):567-72
pubmed: 21782416
Biol Psychiatry. 2015 Apr 15;77(8):729-39
pubmed: 25599931
Gene Ther. 2018 Apr;25(2):83-92
pubmed: 29523880
Neurobiol Dis. 2013 Jan;49:137-47
pubmed: 22940630
Neuron. 2007 Nov 21;56(4):621-39
pubmed: 18031681
Cell Metab. 2011 Sep 7;14(3):365-77
pubmed: 21907142
J Neurosci. 2006 Jun 14;26(24):6573-82
pubmed: 16775145
Neurobiol Aging. 2019 Mar;75:25-37
pubmed: 30508733
Nat Rev Neurosci. 2020 Mar;21(3):153-168
pubmed: 32042144
Science. 2006 Oct 27;314(5799):664-6
pubmed: 16990514
Science. 2016 Sep 30;353(6307):1536-1541
pubmed: 27708103
Hippocampus. 2000;10(1):47-56
pubmed: 10706216
Clin Transl Sci. 2018 Nov;11(6):540-552
pubmed: 29877608
Biol Psychiatry. 2021 Apr 15;89(8):745-756
pubmed: 32223911
PLoS One. 2019 Nov 14;14(11):e0225206
pubmed: 31725765
J Vis Exp. 2019 Jan 29;(143):
pubmed: 30774140
J Neurosci. 2009 Apr 15;29(15):4964-71
pubmed: 19369565
J Biol Chem. 1951 Nov;193(1):265-75
pubmed: 14907713
PLoS Pathog. 2020 Oct 29;16(10):e1009004
pubmed: 33119726